156 results on '"Powell FL"'
Search Results
2. CNS changes in chronic hypoxia
- Author
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Aguilar N, NM, Kim, CB, Powell, FL, and Reid, SG
- Published
- 2001
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3. High Prevalence of Obstructive Sleep Apnea in Patients with Moderate to Severe Chronic Obstructive Pulmonary Disease
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Soler, X, Gaio, E, Powell, FL, Ramsdell, JW, Loredo, JS, Malhotra, A, and Ries, AL
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Male ,Chronic Obstructive ,Sleep Apnea ,Polysomnography ,Clinical Sciences ,Respiratory System ,urologic and male genital diseases ,Severity of Illness Index ,chronic obstructive pulmonary disease ,Pulmonary Disease ,Clinical Research ,Surveys and Questionnaires ,Behavioral and Social Science ,Humans ,overlap ,Prospective Studies ,Lung ,obstructive sleep apnea ,Original Research ,Aged ,Obstructive ,Rehabilitation ,sleep-disordered breathing ,Middle Aged ,pulmonary rehabilitation ,nervous system diseases ,respiratory tract diseases ,Oxygen ,Physical Rehabilitation ,Multivariate Analysis ,Respiratory ,Linear Models ,Quality of Life ,Female ,Sleep Research - Abstract
Copyright © 2015 by the American Thoracic Society. Rationale: When obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) coexist in the so-called "overlap" syndrome,a high risk formortalityandmorbidity hasbeenreported.There is controversy about the prevalence of OSA in people affected by COPD. Objectives: The purpose of this study was to investigate objective meaures of sleep-disordered breathing in patients with moderate to severe COPD to test the hypothesis that COPD is associated with an increased prevalence of OSA. Methods: Fifty-four patients (54% men) with moderate to severe COPD were enrolled prospectively (mean±SD, FEV1 = 42.8± 19.8% predicted, and FEV1/FVC = 42.3±13.1). Twenty patients (37%) were on supplemental oxygen at baseline. Exercise tolerance; questionnaires related to symptoms, sleep, and quality of life; and home polysomnography were obtained. Measurements and Main Results: Forty-four patients had full polysomnography suitable for analysis. OSA (apnea-hypopnea index>5/h) was present in 29 subjects (65.9%). Sleep efficiency was poor in 45% of subjects. Conclusions: OSA is highly prevalent in patients with moderate to severe COPD referred to pulmonary rehabilitation. Sleep quality is also poor among this selected group. These patients have greaterthan- expected sleep-disordered breathing, which could be an important contributory factor to morbidity and mortality. Pulmonary rehabilitation programs should consider including a sleep assessment in patients with moderate to severe COPD and interventions when indicated to help reduce the impact of OSA in COPD.
- Published
- 2015
4. Tibetans exhibit lower hemoglobin concentration and decreased heart response to hypoxia during poikilocapnia at intermediate altitude relative to Han Chinese.
- Author
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Moya EA, Yu JJ, Brown S, Gu W, Lawrence ES, Carlson R, Brandes A, Wegeng W, Amann K, McIntosh SE, Powell FL, and Simonson TS
- Abstract
Background: High-altitude populations exhibit distinct cellular, respiratory, and cardiovascular phenotypes, some of which provide adaptive advantages to hypoxic conditions compared to populations with sea-level ancestry. Studies performed in populations with a history of high-altitude residence, such as Tibetans, support the idea that many of these phenotypes may be shaped by genomic features that have been positively selected for throughout generations. We hypothesize that such traits observed in Tibetans at high altitude also occur in Tibetans living at intermediate altitude, even in the absence of severe sustained hypoxia., Methodology: We studied individuals of high-altitude ancestry (Tibetans, n = 17 females; n = 12 males) and sea-level ancestry (Han Chinese, n = 6 females; n = 10 males), both who had been living at ∼1300 m (∼4327 ft) for at least 18 months. We measured hemoglobin concentration ([Hb]), hypoxic ventilatory response (HVR), and hypoxic heart rate response (HHRR) with end-tidal CO
2 (PetCO2 ) held constant (isocapnia) or allowed to decrease with hypoxic hyperventilation (poikilocapnia). We also quantified the contribution of CO2 on ventilation and heart rate by calculating the differences of isocapnic versus poikilocapnic hypoxic conditions (Δ V ˙ I /ΔPetCO2 and ΔHR/ΔPetCO2 , respectively)., Results: Male Tibetans had lower [Hb] compared to Han Chinese males ( p < 0.05), consistent with reports for individuals from these populations living at high altitude and sea level. Measurements of ventilation (resting ventilation, HVR, and PetCO2 ) were similar for both groups. Heart rate responses to hypoxia were similar in both groups during isocapnia; however, HHRR in poikilocapnia was reduced in the Tibetan group ( p < 0.03), and the heart rate response to CO2 in hypoxia was lower in Tibetans relative to Han Chinese ( p < 0.01)., Conclusion: These results suggest that Tibetans living at intermediate altitude have blunted cardiac responses in the context of hypoxia. Hence, only some of the phenotypes observed in Tibetans living at high altitude are observed in Tibetans living at intermediate altitude. Whereas blunted cardiac responses to hypoxia is revealed at intermediate altitudes, manifestation of other physiological adaptations to high altitude may require exposure to more severe levels of hypoxia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Moya, Yu, Brown, Gu, Lawrence, Carlson, Brandes, Wegeng, Amann, McIntosh, Powell and Simonson.)- Published
- 2024
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5. The normal distribution of the hypoxic ventilatory response and methodological impacts: a meta-analysis and computational investigation.
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Oeung B, Pham K, Olfert IM, Zerda DJ, Gaio E, Powell FL, and Heinrich EC
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- Humans, Normal Distribution, Oxygen, Respiration, Altitude, Hypoxia
- Abstract
The hypoxic ventilatory response (HVR) is the increase in breathing in response to reduced arterial oxygen pressure. Over several decades, studies have revealed substantial population-level differences in the magnitude of the HVR as well as significant inter-individual variation. In particular, low HVRs occur frequently in Andean high-altitude native populations. However, our group conducted hundreds of HVR measures over several years and commonly observed low responses in sea-level populations as well. As a result, we aimed to determine the normal HVR distribution, whether low responses were common, and to what extent variation in study protocols influence these findings. We conducted a comprehensive search of the literature and examined the distributions of HVR values across 78 studies that utilized step-down/steady-state or progressive hypoxia methods in untreated, healthy human subjects. Several studies included multiple datasets across different populations or experimental conditions. In the final analysis, 72 datasets reported mean HVR values and 60 datasets provided raw HVR datasets. Of the 60 datasets reporting raw HVR values, 35 (58.3%) were at least moderately positively skewed (skew > 0.5), and 21 (35%) were significantly positively skewed (skew > 1), indicating that lower HVR values are common. The skewness of HVR distributions does not appear to be an artifact of methodology or the unit with which the HVR is reported. Further analysis demonstrated that the use of step-down hypoxia versus progressive hypoxia methods did not have a significant impact on average HVR values, but that isocapnic protocols produced higher HVRs than poikilocapnic protocols. This work provides a reference for expected HVR values and illustrates substantial inter-individual variation in this key reflex. Finally, the prevalence of low HVRs in the general population provides insight into our understanding of blunted HVRs in high-altitude adapted groups. KEY POINTS: The hypoxic ventilatory response (HVR) plays a crucial role in determining an individual's predisposition to hypoxia-related pathologies. There is notable variability in HVR sensitivity across individuals as well as significant population-level differences. We report that the normal distribution of the HVR is positively skewed, with a significant prevalence of low HVR values amongst the general healthy population. We also find no significant impact of the experimental protocol used to induce hypoxia, although HVR is greater with isocapnic versus poikilocapnic methods. These results provide insight into the normal distribution of the HVR, which could be useful in clinical decisions of diseases related to hypoxaemia. Additionally, the low HVR values found within the general population provide insight into the genetic adaptations found in populations residing in high altitudes., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)
- Published
- 2023
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6. Time Domains of Hypoxia Responses and -Omics Insights.
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Yu JJ, Non AL, Heinrich EC, Gu W, Alcock J, Moya EA, Lawrence ES, Tift MS, O'Brien KA, Storz JF, Signore AV, Khudyakov JI, Milsom WK, Wilson SM, Beall CM, Villafuerte FC, Stobdan T, Julian CG, Moore LG, Fuster MM, Stokes JA, Milner R, West JB, Zhang J, Shyy JY, Childebayeva A, Vázquez-Medina JP, Pham LV, Mesarwi OA, Hall JE, Cheviron ZA, Sieker J, Blood AB, Yuan JX, Scott GR, Rana BK, Ponganis PJ, Malhotra A, Powell FL, and Simonson TS
- Abstract
The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yu, Non, Heinrich, Gu, Alcock, Moya, Lawrence, Tift, O'Brien, Storz, Signore, Khudyakov, Milsom, Wilson, Beall, Villafuerte, Stobdan, Julian, Moore, Fuster, Stokes, Milner, West, Zhang, Shyy, Childebayeva, Vázquez-Medina, Pham, Mesarwi, Hall, Cheviron, Sieker, Blood, Yuan, Scott, Rana, Ponganis, Malhotra, Powell and Simonson.)
- Published
- 2022
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7. Expression and activation of the ketone body receptor HCAR2/GPR109A promotes preservation of retinal endothelial cell barrier function.
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Abdelrahman AA, Powell FL, Jadeja RN, Jones MA, Thounaojam MC, Bartoli M, Al-Shabrawey M, and Martin PM
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- Animals, Blood-Retinal Barrier metabolism, Carrier Proteins metabolism, Endothelial Cells metabolism, Ketones metabolism, Ketones therapeutic use, Mice, RNA, Small Interfering therapeutic use, Diabetic Retinopathy metabolism, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled metabolism, Retinal Diseases metabolism
- Abstract
Preservation of retinal barrier function is critical to maintenance of retinal health. Therefore, it is not surprising that loss of barrier integrity is a pathologic feature common to degenerative retinal diseases such as diabetic retinopathy. Our prior studies demonstrate the importance of hydroxycarboxylic acid receptor 2/GPR109A (HCAR2/GPR109A) expression in the retinal pigment epithelium (RPE) to outer retinal barrier integrity. However, whether HCAR2/GPR109A is expressed in retinal endothelial cells and has a similar relationship to inner blood retinal barrier regulation is not known. In the current study, we examined relevance of receptor expression to endothelial cell dependent-blood retinal barrier integrity. siRNA technology was used to modulate HCAR2/GPR109A expression in human retinal endothelial cells (HRECs). Cells were cultured in the presence or absence of VEGF, a pro-inflammatory stimulus, and/or various concentrations of the HCAR2/GPR109A-specific agonist beta-hydyroxybutyrate (BHB). HCAR2/GPR109A expression was monitored by qPCR and electrical cell impedance sensing (ECIS) was used to evaluate barrier function. Complementary in vivo studies were conducted in wildtype and HCAR2/GPR109A knockout mice treated intraperitoneally with lipopolysaccharide and/or BHB. Vascular leakage was monitored using fluorescein angiography and Western blot analyses of albumin extravasation. Additionally, retinal function was evaluated by OptoMotry. Decreased (siRNA knockdown) or absent (gene knockout) HCAR2/GPR109A expression was associated with impaired barrier function both in vitro and in vivo. BHB treatment provided some protection, limiting disruptions in retinal barrier integrity and function; an effect that was found to be receptor (HCAR2/GPR109A)-dependent. Collectively, the present studies support a key role for HCAR2/GPR109A in regulating blood-retinal barrier integrity and highlight the therapeutic potential of the receptor toward preventing and treating retinal diseases such as diabetic retinopathy in which compromised barrier function is paramount., (Copyright © 2022. Published by Elsevier Ltd.)
- Published
- 2022
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8. Autonomous regulation of retinal insulin biosynthesis in diabetes.
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Jones MA, Jadeja RN, Flandrin O, Abdelrahman AA, Thounojam MC, Thomas S, Dai C, Xiao H, Chen JK, Smith SB, Bartoli M, Martin PM, and Powell FL
- Subjects
- Animals, Insulin pharmacology, Mice, RNA, Messenger metabolism, Retina metabolism, Diabetes Mellitus, Experimental metabolism, Diabetic Retinopathy metabolism, Neurodegenerative Diseases
- Abstract
Diabetic retinopathy (DR) is a neurodegenerative disease that results as a complication of dysregulated glucose metabolism, or diabetes. The signaling of insulin is lost or dampened in diabetes, but this hormone has also been shown to be an important neurotrophic factor which supports neurons of the brain. The role of local insulin synthesis and secretion in the retina, however, is unclear. We have investigated whether changes in local insulin synthesis occur in the diabetic retina and in response to stressors known to initiate retinal neurodegenerative processes. The expression of insulin and its cleavage product, c-peptide, were examined in retinas of a Type I diabetes animal model and human postmortem donors with DR. We detected mRNAs for insulin I (Ins1), insulin II (Ins2) and human insulin (Ins) by quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization. Using an ex-vivo system, isolated neuroretinas and retinal pigmented epithelium (RPE) layers were exposed to glycemic, oxidative and inflammatory environments to measure insulin gene transcripts produced de novo in the retina under disease-relevant conditions. The expression of insulin in the retina was altered with the progression of diabetes in STZ mice and donors with DR. Transcription factors for insulin, were simultaneously expressed in a pattern matching insulin genes. Furthermore, de novo insulin mRNA in isolated retinas was induced by acute stress. RPE explants displayed the most pronounced changes in Ins1 and Ins2. This data reveals that the retina, like the brain, is an organ capable of producing local insulin and this synthesis is altered in diabetes., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
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9. Impacts of Changes in Atmospheric O 2 on Human Physiology. Is There a Basis for Concern?
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Keeling RF, Powell FL, Shaffer G, Robbins PA, and Simonson TS
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Concern is often voiced over the ongoing loss of atmospheric O
2 . This loss, which is caused by fossil-fuel burning but also influenced by other processes, is likely to continue at least for the next few centuries. We argue that this loss is quite well understood, and the eventual decrease is bounded by the fossil-fuel resource base. Because the atmospheric O2 reservoir is so large, the predicted relative drop in O2 is very small even for extreme scenarios of future fossil-fuel usage which produce increases in atmospheric CO2 sufficient to cause catastrophic climate changes. At sea level, the ultimate drop in oxygen partial pressure will be less than 2.5 mm Hg out of a baseline of 159 mmHg. The drop by year 2300 is likely to be between 0.5 and 1.3 mmHg. The implications for normal human health is negligible because respiratory O2 consumption in healthy individuals is only weakly dependent on ambient partial pressure, especially at sea level. The impacts on top athlete performance, on disease, on reproduction, and on cognition, will also be very small. For people living at higher elevations, the implications of this loss will be even smaller, because of a counteracting increase in barometric pressure at higher elevations due to global warming., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Keeling, Powell, Shaffer, Robbins and Simonson.)- Published
- 2021
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10. Inactivation of Endothelial ADAM17 Reduces Retinal Ischemia-Reperfusion Induced Neuronal and Vascular Damage.
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Gutsaeva DR, Shalaby L, Powell FL, Thounaojam MC, Abouhish H, Wetzstein SA, Jadeja RN, Kwok HF, Martin PM, and Bartoli M
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- ADAM17 Protein deficiency, Albumins metabolism, Animals, Apoptosis genetics, Capillary Permeability, Caspase 3 genetics, Caspase 3 metabolism, Cell Adhesion, Disease Models, Animal, Endothelium, Vascular metabolism, Endothelium, Vascular pathology, Gene Expression Regulation, Leukocytes metabolism, Leukocytes pathology, Leukostasis metabolism, Leukostasis pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Oxidative Stress, Receptors, Nerve Growth Factor genetics, Receptors, Nerve Growth Factor metabolism, Reperfusion Injury metabolism, Reperfusion Injury pathology, Retinal Degeneration metabolism, Retinal Degeneration pathology, Retinal Ganglion Cells pathology, ADAM17 Protein genetics, Leukostasis genetics, Reperfusion Injury genetics, Retinal Degeneration genetics, Retinal Ganglion Cells metabolism
- Abstract
Retinal ischemia contributes to visual impairment in ischemic retinopathies. A disintegrin and metalloproteinase ADAM17 is implicated in multiple vascular pathologies through its ability to regulate inflammatory signaling via ectodomain shedding. We investigated the role of endothelial ADAM17 in neuronal and vascular degeneration associated with retinal ischemia reperfusion (IR) injury using mice with conditional inactivation of ADAM17 in vascular endothelium. ADAM17Cre-flox and control ADAM17flox mice were subjected to 40 min of pressure-induced retinal ischemia, with the contralateral eye serving as control. Albumin extravasation and retinal leukostasis were evaluated 48 h after reperfusion. Retinal morphometric analysis was conducted 7 days after reperfusion. Degenerate capillaries were assessed by elastase digest and visual function was evaluated by optokinetic test 14 and 7 days following ischemia, respectively. Lack of ADAM17 decreased vascular leakage and reduced retinal thinning and ganglion cell loss in ADAM17Cre-flox mice. Further, ADAM17Cre-flox mice exhibited a remarkable reduction in capillary degeneration following IR. Decrease in neurovascular degeneration in ADAM17Cre-flox mice correlated with decreased activation of caspase-3 and was associated with reduction in oxidative stress and retinal leukostasis. In addition, knockdown of ADAM17 resulted in decreased cleavage of p75NTR, the process known to be associated with retinal cell apoptosis. A decline in visual acuity evidenced by decrease in spatial frequency threshold observed in ADAM17flox mice was partially restored in ADAM17-endothelial deficient mice. The obtained results provide evidence that endothelial ADAM17 is an important contributor to IR-induced neurovascular damage in the retina and suggest that interventions directed at regulating ADAM17 activity can be beneficial for alleviating the consequences of retinal ischemia.
- Published
- 2020
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11. Inhibition of HDAC6 Attenuates Diabetes-Induced Retinal Redox Imbalance and Microangiopathy.
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Abouhish H, Thounaojam MC, Jadeja RN, Gutsaeva DR, Powell FL, Khriza M, Martin PM, and Bartoli M
- Abstract
We investigated the contributing role of the histone deacetylase 6 (HDAC6) to the early stages of diabetic retinopathy (DR). Furthermore, we examined the mechanism of action of HDAC6 in human retinal endothelial cells (HuREC) exposed to glucidic stress. Streptozotocin-induced diabetic rats (STZ-rats), a rat model of type 1 diabetes, were used as model of DR. HDAC6 expression and activity were increased in human diabetic postmortem donors and STZ-rat retinas and were augmented in HuREC exposed to glucidic stress (25 mM glucose). Administration of the HDAC6 specific inhibitor Tubastatin A (TS) (10 mg/kg) prevented retinal microvascular hyperpermeability and up-regulation of inflammatory markers. Furthermore, in STZ-rats, TS decreased the levels of senescence markers and rescued the expression and activity of the histone deacetylase sirtuin 1 (SIRT1), while downregulating the levels of free radicals and of the redox stress markers 4-hydroxynonenal (4-HNE) and nitrotyrosine (NT). The antioxidant effects of TS, consequent to HDAC6 inhibition, were associated with preservation of Nrf2-dependent gene expression and up-regulation of thioredoxin-1 activity. In vitro data, obtained from HuREC, exposed to glucidic stress, largely replicated the in vivo results further confirming the antioxidant effects of HDAC6 inhibition by TS in the diabetic rat retina. In summary, our data implicate HDAC6 activation in mediating hyperglycemia-induced retinal oxidative/nitrative stress leading to retinal microangiopathy and, potentially, DR.
- Published
- 2020
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12. Mechanistic dissection of diabetic retinopathy using the protein-metabolite interactome.
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Patrick AT, He W, Madu J, Sripathi SR, Choi S, Lee K, Samson FP, Powell FL, Bartoli M, Jee D, Gutsaeva DR, and Jahng WJ
- Abstract
Purpose: The current study aims to determine the molecular mechanisms of diabetic retinopathy (DR) using the protein-protein interactome and metabolome map. We examined the protein network of novel biomarkers of DR for direct (physical) and indirect (functional) interactions using clinical target proteins in different models., Methods: We used proteomic tools including 2-dimensional gel electrophoresis, mass spectrometry analysis, and database search for biomarker identification using in vivo murine and human model of diabetic retinopathy and in vitro model of oxidative stress. For the protein interactome and metabolome mapping, various bioinformatic tools that include STRING and OmicsNet were used., Results: We uncovered new diabetic biomarkers including prohibitin (PHB), dynamin 1, microtubule-actin crosslinking factor 1, Toll-like receptor (TLR 7), complement activation, as well as hypothetical proteins that include a disintegrin and metalloproteinase (ADAM18), vimentin III, and calcium-binding C2 domain-containing phospholipid-binding switch (CAC2PBS) using a proteomic approach. Proteome networks of protein interactions with diabetic biomarkers were established using known DR-related proteome data. DR metabolites were interconnected to establish the metabolome map. Our results showed that mitochondrial protein interactions were changed during hyperglycemic conditions in the streptozotocin-treated murine model and diabetic human tissue., Conclusions: Our interactome mapping suggests that mitochondrial dysfunction could be tightly linked to various phases of DR pathogenesis including altered visual cycle, cytoskeletal remodeling, altered lipid concentration, inflammation, PHB depletion, tubulin phosphorylation, and altered energy metabolism. The protein-metabolite interactions in the current network demonstrate the etiology of retinal degeneration and suggest the potential therapeutic approach to treat DR., Competing Interests: Conflict of interestNone declared., (© Springer Nature Switzerland AG 2020.)
- Published
- 2020
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13. Relationships Between Chemoreflex Responses, Sleep Quality, and Hematocrit in Andean Men and Women.
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Heinrich EC, Orr JE, Gilbertson D, Anza-Ramirez C, DeYoung PN, Djokic MA, Corante N, Vizcardo-Galindo G, Macarlupu JL, Gaio E, Powell FL, Malhotra A, Villafuerte FC, and Simonson TS
- Abstract
Andean highlanders are challenged by chronic hypoxia and many exhibit elevated hematocrit (Hct) and blunted ventilation compared to other high-altitude populations. While many Andeans develop Chronic Mountain Sickness (CMS) and excessive erythrocytosis, Hct varies markedly within Andean men and women and may be driven by individual differences in ventilatory control and/or sleep events which exacerbate hypoxemia. To test this hypothesis, we quantified relationships between resting ventilation and ventilatory chemoreflexes, sleep desaturation, breathing disturbance, and Hct in Andean men and women. Ventilatory measures were made in 109 individuals ( n = 63 men; n = 46 women), and sleep measures in 45 of these participants ( n = 22 men; n = 23 women). In both men and women, high Hct was associated with low daytime SpO
2 ( p < 0.001 and p < 0.002, respectively) and decreased sleep SpO2 (mean, nadir, and time <80%; all p < 0.02). In men, high Hct was also associated with increased end-tidal PCO2 ( p < 0.009). While ventilatory responses to hypoxia and hypercapnia did not predict Hct, decreased hypoxic ventilatory responses were associated with lower daytime SpO2 in men ( p < 0.01) and women ( p < 0.009) and with lower nadir sleep SpO2 in women ( p < 0.02). Decreased ventilatory responses to CO2 were associated with more time below 80% SpO2 during sleep in men ( p < 0.05). The obstructive apnea index and apnea-hypopnea index also predicted Hct and CMS scores in men after accounting for age, BMI, and SpO2 during sleep. Finally, heart rate response to hypoxia was lower in men with higher Hct ( p < 0.0001). These data support the idea that hypoventilation and decreased ventilatory sensitivity to hypoxia are associated with decreased day time and nighttime SpO2 levels that may exacerbate the stimulus for erythropoiesis in Andean men and women. However, interventional and longitudinal studies are required to establish the causal relationships between these associations., (Copyright © 2020 Heinrich, Orr, Gilbertson, Anza-Ramirez, DeYoung, Djokic, Corante, Vizcardo-Galindo, Macarlupu, Gaio, Powell, Malhotra, Villafuerte and Simonson.)- Published
- 2020
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14. Neuronal HIF-1α in the nucleus tractus solitarius contributes to ventilatory acclimatization to hypoxia.
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Moya EA, Go A, Kim CB, Fu Z, Simonson TS, and Powell FL
- Subjects
- Acclimatization, Animals, Mice, Neurons, Respiratory Center, Hypoxia, Solitary Nucleus
- Abstract
Key Points: We hypothesized that hypoxia inducible factor 1α (HIF-1α) in CNS respiratory centres is necessary for ventilatory acclimatization to hypoxia (VAH); VAH is a time-dependent increase in baseline ventilation and the hypoxic ventilatory response (HVR) occurring over days to weeks of chronic sustained hypoxia (CH). Constitutive deletion of HIF-1α in CNS neurons in transgenic mice tended to blunt the increase in HVR that occurs in wild-type mice with CH. Conditional deletion of HIF-1α in glutamatergic neurons of the nucleus tractus solitarius during CH significantly decreased ventilation in acute hypoxia but not normoxia in CH mice. These effects are not explained by changes in metabolic rate, nor CO
2 , and there were no changes in the HVR in normoxic mice. HIF-1α mediated changes in gene expression in CNS respiratory centres are necessary in addition to plasticity of arterial chemoreceptors for normal VAH., Abstract: Chronic hypoxia (CH) produces a time-dependent increase of resting ventilation and the hypoxic ventilatory response (HVR) that is called ventilatory acclimatization to hypoxia (VAH). VAH involves plasticity in arterial chemoreceptors and the CNS [e.g. nucleus tractus solitarius (NTS)], although the signals for this plasticity are not known. We hypothesized that hypoxia inducible factor 1α (HIF-1α), an O2 -sensitive transcription factor, is necessary in the NTS for normal VAH. We tested this in two mouse models using loxP-Cre gene deletion. First, HIF-1α was constitutively deleted in CNS neurons (CNS-HIF-1α-/- ) by breeding HIF-1α floxed mice with mice expressing Cre-recombinase driven by the calcium/calmodulin-dependent protein kinase IIα promoter. Second, HIF-1α was deleted in NTS neurons in adult mice (NTS-HIF-1α-/- ) by microinjecting adeno-associated virus that expressed Cre-recombinase in HIF-1α floxed mice. In normoxic control mice, HIF-1α deletion in the CNS or NTS did not affect ventilation, nor the acute HVR (10-15 min hypoxic exposure). In mice acclimatized to CH for 1 week, ventilation in hypoxia was blunted in CNS-HIF-1α-/- and significantly decreased in NTS-HIF-1α-/- compared to control mice (P < 0.0001). These changes were not explained by differences in metabolic rate or CO2 . Immunofluorescence showed that HIF-1α deletion in NTS-HIF-1α-/- was restricted to glutamatergic neurons. The results indicate that HIF-1α is a necessary signal for VAH and the previously described plasticity in glutamatergic neurotransmission in the NTS with CH. HIF-1α deletion had no effect on the increase in normoxic ventilation with acclimatization to CH, indicating this is a distinct mechanism from the increased HVR with VAH., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)- Published
- 2020
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15. Inhibiting microRNA-144 potentiates Nrf2-dependent antioxidant signaling in RPE and protects against oxidative stress-induced outer retinal degeneration.
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Jadeja RN, Jones MA, Abdelrahman AA, Powell FL, Thounaojam MC, Gutsaeva D, Bartoli M, and Martin PM
- Subjects
- 3' Untranslated Regions, Animals, Cell Line, Humans, Male, Mice, Models, Biological, RNA Interference, Retinal Degeneration pathology, Antioxidants metabolism, MicroRNAs genetics, NF-E2-Related Factor 2 metabolism, Oxidative Stress, Retinal Degeneration etiology, Retinal Degeneration metabolism, Retinal Pigment Epithelium metabolism, Signal Transduction drug effects
- Abstract
The retinal pigment epithelium (RPE) is consistently exposed to high levels of pro-oxidant and inflammatory stimuli. As such, under normal conditions the antioxidant machinery in the RPE cell is one of the most efficient in the entire body. However, antioxidant defense mechanisms are often impacted negatively by the process of aging and/or degenerative disease leaving RPE susceptible to damage which contributes to retinal dysfunction. Thus, understanding better the mechanisms governing antioxidant responses in RPE is critically important. Here, we evaluated the role of the redox sensitive microRNA miR-144 in regulation of antioxidant signaling in human and mouse RPE. In cultured human RPE, miR-144-3p and miR-144-5p expression was upregulated in response to pro-oxidant stimuli. Likewise, overexpression of miR-144-3p and -5p using targeted miR mimics was associated with reduced expression of Nrf2 and downstream antioxidant target genes (NQO1 and GCLC), reduced levels of glutathione and increased RPE cell death. Alternately, some protection was conferred against the above when miR-144-3p and miR-144-5p expression was suppressed using antagomirs. Expression analyses revealed a higher conservation of miR-144-3p expression across species and additionally, the presence of two potential Nrf2 binding sites in the 3p sequence compared to only one in the 5p sequence. Thus, we evaluated the impact of miR-144-3p expression in the retinas of mice in which a robust pro-oxidant environment was generated using sodium iodate (SI). Subretinal injection of miR-144-3p antagomir in SI mice preserved retinal integrity and function, decreased oxidative stress, limited apoptosis and enhanced antioxidant gene expression. Collectively, the present work establishes miR-144 as a potential target for preventing and treating degenerative retinal diseases in which oxidative stress is paramount and RPE is prominently affected (e.g., age-related macular degeneration and diabetic retinopathy)., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2020
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16. MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities.
- Author
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Thounaojam MC, Jadeja RN, Warren M, Powell FL, Raju R, Gutsaeva D, Khurana S, Martin PM, and Bartoli M
- Abstract
Stress-associated premature senescence (SAPS) is involved in retinal microvascular injury and diabetic retinopathy. We have investigated the role and mode of action of miR-34a in retinal endothelial cells senescence in response to glucidic stress. Human retinal microvascular endothelial cells (HuREC) were exposed to glucidic stress (high glucose (HG) = 25 mM d-glucose) and compared to cells exposed to normal glucose (NG = 5 mM) or the osmotic control l-glucose (LG = 25 mM). HG stimulation of HuREC increased the expression of miR-34a and induced cellular senescence. HG also increased the expression of p16ink4a and p21waf1, while decreasing the histone deacetylase SIRT1. These effects were associated with diminished mitochondrial function and loss of mitochondrial biogenesis factors (i.e., PGC-1α, NRF1, and TFAM). Transfection of the cells with miR-34a inhibitor (IB) halted HG-induced mitochondrial dysfunction and up-regulation of senescence-associated markers, whereas miR-34a mimic promoted cellular senescence and mitochondrial dysfunction. Moreover, HG lowered levels of the mitochondrial antioxidants TrxR2 and SOD2, an effect blunted by miR-34a IB, and promoted by miR-34a mimic. 3'-UTR (3'-untranslated region) reporter assay of both genes validated TrxR2 as a direct target of miR-34a, but not SOD2. Our results show that miR-34a is a key player of HG-induced SAPS in retinal endothelial cells via multiple pathways involved in mitochondrial function and biogenesis.
- Published
- 2019
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17. Renal iron accelerates the progression of diabetic nephropathy in the HFE gene knockout mouse model of iron overload.
- Author
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Chaudhary K, Chilakala A, Ananth S, Mandala A, Veeranan-Karmegam R, Powell FL, Ganapathy V, and Gnana-Prakasam JP
- Subjects
- Animals, Deferiprone pharmacology, Deferiprone therapeutic use, Diabetes Mellitus, Experimental metabolism, Diabetic Nephropathies drug therapy, Disease Progression, Iron Chelating Agents pharmacology, Iron Chelating Agents therapeutic use, Male, Mice, Mice, Knockout, Renin biosynthesis, Renin-Angiotensin System drug effects, Diabetic Nephropathies genetics, Diabetic Nephropathies metabolism, Hemochromatosis Protein genetics, Hemochromatosis Protein metabolism, Iron metabolism, Iron Overload genetics, Iron Overload metabolism, Kidney metabolism
- Abstract
Diabetic nephropathy (DN) is the most common cause of end-stage renal disease associated with high mortality worldwide. Increases in iron levels have been reported in diabetic rat kidneys as well as in human urine of patients with diabetes. In addition, a low-iron diet or iron chelators delay the progression of DN in patients with diabetes and in animal models of diabetes. Possible maladaptive mechanisms of organ damage by tissue iron accumulation have not been well studied. We recently reported that iron induced the retinal renin-angiotensin system (RAS) and accelerated the progression of diabetic retinopathy. However, whether iron regulates the systemic RAS is unknown. To explore if iron alters the expression of intrarenal RAS and its role in the progression of DN, we used the high Fe iron (HFE) knockout mouse, a genetic model of systemic iron overload. We found that diabetes upregulated the expression of iron regulatory proteins and augmented tissue iron accumulation in the kidneys of both type 1 and type 2 diabetic mouse models. Iron accumulation in the kidneys of HFE knockout mice was associated with increase in serum and intrarenal renin expression. Induction of diabetes in HFE knockout mice using streptozotocin caused a much higher accumulation of renal iron and accelerated the progression of nephropathy compared with diabetic wild-type mice. Treatment of diabetic mice with the iron chelator deferiprone reversed the renin upregulation and reduced kidney injury. Thus, our results establish a new link between renal iron and RAS activity. Exploring the mechanisms of iron-induced RAS activation further may have a significant therapeutic impact on hypertension and DN.
- Published
- 2019
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18. Cognitive function and mood at high altitude following acclimatization and use of supplemental oxygen and adaptive servoventilation sleep treatments.
- Author
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Heinrich EC, Djokic MA, Gilbertson D, DeYoung PN, Bosompra NO, Wu L, Anza-Ramirez C, Orr JE, Powell FL, Malhotra A, and Simonson TS
- Subjects
- Acclimatization, Adult, Altitude, Female, Humans, Male, Polysomnography, Self Report, Sleep Apnea, Central psychology, Treatment Outcome, Young Adult, Affect physiology, Cognition physiology, Interactive Ventilatory Support methods, Oxygen administration & dosage, Sleep Apnea, Central therapy
- Abstract
Impairments in cognitive function, mood, and sleep quality occur following ascent to high altitude. Low oxygen (hypoxia) and poor sleep quality are both linked to impaired cognitive performance, but their independent contributions at high altitude remain unknown. Adaptive servoventilation (ASV) improves sleep quality by stabilizing breathing and preventing central apneas without supplemental oxygen. We compared the efficacy of ASV and supplemental oxygen sleep treatments for improving daytime cognitive function and mood in high-altitude visitors (N = 18) during acclimatization to 3,800 m. Each night, subjects were randomly provided with ASV, supplemental oxygen (SpO2 > 95%), or no treatment. Each morning subjects completed a series of cognitive function tests and questionnaires to assess mood and multiple aspects of cognitive performance. We found that both ASV and supplemental oxygen (O2) improved daytime feelings of confusion (ASV: p < 0.01; O2: p < 0.05) and fatigue (ASV: p < 0.01; O2: p < 0.01) but did not improve other measures of cognitive performance at high altitude. However, performance improved on the trail making tests (TMT) A and B (p < 0.001), the balloon analog risk test (p < 0.0001), and the psychomotor vigilance test (p < 0.01) over the course of three days at altitude after controlling for effects of sleep treatments. Compared to sea level, subjects reported higher levels of confusion (p < 0.01) and performed worse on the TMT A (p < 0.05) and the emotion recognition test (p < 0.05) on nights when they received no treatment at high altitude. These results suggest that stabilizing breathing (ASV) or increasing oxygenation (supplemental oxygen) during sleep can reduce feelings of fatigue and confusion, but that daytime hypoxia may play a larger role in other cognitive impairments reported at high altitude. Furthermore, this study provides evidence that some aspects of cognition (executive control, risk inhibition, sustained attention) improve with acclimatization., Competing Interests: ResMed provided a philanthropic donation to UCSD in support of a sleep center but had no role in funding, study design, data collection and analysis, decision to publish, or preparation of this research. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (employment, consultancy, patents, products in development, marketed products), or nonfinancial interest (personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter discussed in this article.
- Published
- 2019
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19. Monosodium Urate Contributes to Retinal Inflammation and Progression of Diabetic Retinopathy.
- Author
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Thounaojam MC, Montemari A, Powell FL, Malla P, Gutsaeva DR, Bachettoni A, Ripandelli G, Repossi A, Tawfik A, Martin PM, Facchiano F, and Bartoli M
- Subjects
- Allopurinol therapeutic use, Animals, Benzbromarone therapeutic use, Diabetes Mellitus, Experimental, Diabetic Retinopathy drug therapy, Diabetic Retinopathy etiology, Humans, Hyperuricemia complications, Inflammation drug therapy, Inflammation etiology, Inflammation immunology, Inflammation pathology, Male, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Rats, Retina drug effects, Retina metabolism, Retina pathology, Risk Factors, Uric Acid blood, Vitreous Body metabolism, Xanthine Oxidase metabolism, Diabetic Retinopathy immunology, Diabetic Retinopathy pathology, Uric Acid adverse effects, Uric Acid metabolism
- Abstract
We have investigated the contributing role of monosodium urate (MSU) to the pathological processes associated with the induction of diabetic retinopathy (DR). In human postmortem retinas and vitreous from donors with DR, we have found a significant increase in MSU levels that correlated with the presence of inflammatory markers and enhanced expression of xanthine oxidase. The same elevation in MSU levels was also detected in serum and vitreous of streptozotocin-induced diabetic rats (STZ-rats) analyzed at 8 weeks of hyperglycemia. Furthermore, treatments of STZ-rats with the hypouricemic drugs allopurinol (50 mg/kg) and benzbromarone (10 mg/kg) given every other day resulted in a significant decrease of retinal and plasma levels of inflammatory cytokines and adhesion factors, a marked reduction of hyperglycemia-induced retinal leukostasis, and restoration of retinal blood-barrier function. These results were associated with effects of the hypouricemic drugs on downregulating diabetes-induced levels of oxidative stress markers as well as expression of components of the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome such as NLRP3, Toll-like receptor 4, and interleukin-1β. The outcomes of these studies support a contributing role of MSU in diabetes-induced retinal inflammation and suggest that asymptomatic hyperuricemia should be considered as a risk factor for DR induction and progression., (© 2019 by the American Diabetes Association.)
- Published
- 2019
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20. Loss of GPR109A/HCAR2 induces aging-associated hepatic steatosis.
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Jadeja RN, Jones MA, Fromal O, Powell FL, Khurana S, Singh N, and Martin PM
- Subjects
- Animals, Cell Line, Fats metabolism, Fatty Liver metabolism, Hepatocytes, Humans, Lipogenesis genetics, Lipogenesis physiology, Mice, Mice, Knockout, Receptors, G-Protein-Coupled genetics, Weight Gain genetics, Aging, Fatty Liver genetics, Receptors, G-Protein-Coupled metabolism
- Abstract
GPR109A agonists have been used for the treatment of obesity however, the role of GPR109A in regulating aging-associated alterations in lipid metabolism is unknown. In this study we used Gpr109a
-/- mice to investigate the effect of aging in the regulation of lipid accumulation. We observed that in mouse and human livers, in addition to Kupffer cells, GPR109A is expressed in hepatocytes. Over 12 months, compared to wild type (WT), Gpr109a-/- mice gained significantly more weight. Food intake and levels of serum lipids were similar among both groups. Compared to age-matched WT mice, 12-months old Gpr109a-/- mice had significantly increased liver weight, hepatic steatosis and serum markers of liver injury. The fatty liver phenotype in Gpr109a-/- mice was associated with increased hepatic expression of lipogenesis genes and decreased expression of lipolysis genes. Gpr109a-/- mice had significantly increased fat tissues, which was associated with significant increase in adipocyte diameter and surface area. Adipose tissue from Gpr109a-/- mice had increased expression of lipogenesis genes; however, expression of lipolytic genes was similar in both groups. Collectively, these results indicate that during aging, GPR109A modulates de novo lipid accumulation in liver and adipose tissue, and its dysregulation can lead to age-associated obesity and hepatic steatosis.- Published
- 2019
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21. Ibuprofen does not reverse ventilatory acclimatization to chronic hypoxia.
- Author
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De La Zerda DJ, Stokes JA, Do J, Go A, Fu Z, and Powell FL
- Subjects
- Analysis of Variance, Animals, Calcium-Binding Proteins metabolism, Disease Models, Animal, Glial Fibrillary Acidic Protein metabolism, Hypoxia pathology, Male, Microfilament Proteins metabolism, Neuroglia drug effects, Rats, Rats, Sprague-Dawley, Respiratory Center drug effects, Solitary Nucleus pathology, Acclimatization drug effects, Cyclooxygenase Inhibitors pharmacology, Hypoxia drug therapy, Hypoxia physiopathology, Ibuprofen pharmacology, Ventilation methods
- Abstract
Ventilatory acclimatization to hypoxia involves an increase in the acute hypoxic ventilatory response that is blocked by non-steroidal anti-inflammatory drugs administered during sustained hypoxia. We tested the hypothesis that inflammatory signals are necessary to sustain ventilatory acclimatization to hypoxia once it is established. Adult, rats were acclimatized to normoxia or chronic hypoxia (CH, [Formula: see text] =70Torr) for 11-12days and treated with ibuprofen or saline for the last 2days of hypoxia. Ventilation, metabolic rate, and arterial blood gas responses to O
2 and CO2 were not affected by ibuprofen after acclimatization had been established. Immunohistochemistry and image analysis showed acute (1h) hypoxia activated microglia in a medullary respiratory center (nucleus tractus solitarius, NTS) and this was blocked by ibuprofen administered from the beginning of hypoxic exposure. Microglia returned to the control state after 7days of CH and were not affected by ibuprofen administered for 2 more days of CH. In contrast, NTS astrocytes were activated by CH but not acute hypoxia and activation was not reversed by administering ibuprofen for the last 2days of CH. Hence, ibuprofen cannot reverse ventilatory acclimatization or astrocyte activation after they have been established by sustained hypoxia. The results are consistent with a model for microglia activation or other ibuprofen-sensitive processes being necessary for the induction but not maintenance of ventilatory acclimatization to hypoxia., (Copyright © 2017 Elsevier B.V. All rights reserved.)- Published
- 2018
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22. AMP-activated Protein Kinase Phosphorylation of Angiotensin-Converting Enzyme 2 in Endothelium Mitigates Pulmonary Hypertension.
- Author
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Zhang J, Dong J, Martin M, He M, Gongol B, Marin TL, Chen L, Shi X, Yin Y, Shang F, Wu Y, Huang HY, Zhang J, Zhang Y, Kang J, Moya EA, Huang HD, Powell FL, Chen Z, Thistlethwaite PA, Yuan ZY, and Shyy JY
- Subjects
- Angiotensin-Converting Enzyme 2, Animals, Disease Models, Animal, Endothelium, Vascular enzymology, Humans, Hypertension, Pulmonary enzymology, Lung enzymology, Lung physiopathology, Mice, Mice, Knockout, Rats, Rats, Sprague-Dawley, AMP-Activated Protein Kinases metabolism, Endothelium, Vascular physiopathology, Hypertension, Pulmonary physiopathology, Peptidyl-Dipeptidase A metabolism
- Abstract
Rationale: Endothelial dysfunction plays an integral role in pulmonary hypertension (PH). AMPK (AMP-activated protein kinase) and ACE2 (angiotensin-converting enzyme 2) are crucial in endothelial homeostasis. The mechanism by which AMPK regulates ACE2 in the pulmonary endothelium and its protective role in PH remain elusive., Objectives: We investigated the role of AMPK phosphorylation of ACE2 Ser680 in ACE2 stability and deciphered the functional consequences of this post-translational modification of ACE2 in endothelial homeostasis and PH., Methods: Bioinformatics prediction, kinase assay, and antibody against phospho-ACE2 Ser680 (p-ACE2 S680) were used to investigate AMPK phosphorylation of ACE2 Ser680 in endothelial cells. Using CRISPR-Cas9 genomic editing, we created gain-of-function ACE2 S680D knock-in and loss-of-function ACE2 knockout (ACE2
-/- ) mouse lines to address the involvement of p-ACE2 S680 and ACE2 in PH. The AMPK-p-ACE2 S680 axis was also validated in lung tissue from humans with idiopathic pulmonary arterial hypertension., Measurements and Main Results: Phosphorylation of ACE2 by AMPK enhanced the stability of ACE2, which increased Ang (angiotensin) 1-7 and endothelial nitric oxide synthase-derived NO bioavailability. ACE2 S680D knock-in mice were resistant to PH as compared with wild-type littermates. In contrast, ACE2-knockout mice exacerbated PH, a similar phenotype found in mice with endothelial cell-specific deletion of AMPKα2. Consistently, the concentrations of phosphorylated AMPK, p-ACE2 S680, and ACE2 were decreased in human lungs with idiopathic pulmonary arterial hypertension., Conclusions: Impaired phosphorylation of ACE2 Ser680 by AMPK in pulmonary endothelium leads to a labile ACE2 and hence is associated with the pathogenesis of PH. Thus, AMPK regulation of the vasoprotective ACE2 is a potential target for PH treatment.- Published
- 2018
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23. Serotonin and Adenosine G-protein Coupled Receptor Signaling for Ventilatory Acclimatization to Sustained Hypoxia.
- Author
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Moya EA and Powell FL
- Abstract
Different patterns of hypoxia evoke different forms of plasticity in the neural control of ventilation. For example, acute intermittent hypoxia produces long term facilitation (LTF) of ventilation, while chronic sustained hypoxia (CH) causes ventilatory acclimatization to hypoxia (VAH). In both LTF and VAH, ventilation in normoxia is greater than normal after the hypoxic stimulus is removed and the acute hypoxic ventilatory response can increase. However, the mechanisms of LTF and VAH are thought to be different based on previous results showing serotonin 5HT
2 receptors, which are G protein coupled receptors (GPCR) that activate GQ signaling, contribute to LTF but not VAH. Newer results show that a different GPCR, namely adenosine A2A receptors and the GS signaling pathway, cause LTF with more severe intermittent hypoxia, i.e., PaO2 = 25-30 Torr for GS versus 35-45 Torr for LTF with the GQ signaling pathway. We hypothesized adenosine A2A receptors and GS signaling are involved in establishing VAH with longer term moderate CH and tested this in adult male rats by measuring ventilatory responses to O2 and CO2 with barometric pressure plethysmography after administering MSX-3 or ketanserin (A2A and 5HT2 antagonists, respectively, both 1 mg/Kg i.p.) during CH for 7 days. Blocking GS or GQ signals throughout CH exposure, significantly decreased VAH. After VAH was established, GQ blockade did not affect ventilation while GS blockade increased VAH. Similar to LTF, data support roles for both GQ and GS pathways in the development of VAH but after VAH has been established, the GS pathway inhibits VAH.- Published
- 2018
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24. Computational model of brain-stem circuit for state-dependent control of hypoglossal motoneurons.
- Author
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Naji M, Komarov M, Krishnan GP, Malhotra A, Powell FL, Rukhadze I, Fenik VB, and Bazhenov M
- Subjects
- Adrenergic Agents pharmacology, Humans, Motor Neurons drug effects, Serotonin Agents pharmacology, Sleep, REM, Tongue innervation, Brain Stem physiopathology, Hypoglossal Nerve physiopathology, Models, Neurological, Motor Neurons physiology, Sleep Apnea, Obstructive physiopathology
- Abstract
In patients with obstructive sleep apnea (OSA), the pharyngeal muscles become relaxed during sleep, which leads to a partial or complete closure of upper airway. Experimental studies suggest that withdrawal of noradrenergic and serotonergic drives importantly contributes to depression of hypoglossal motoneurons and, therefore, may contribute to OSA pathophysiology; however, specific cellular and synaptic mechanisms remain unknown. In this new study, we developed a biophysical network model to test the hypothesis that, to explain experimental observations, the neuronal network for monoaminergic control of excitability of hypoglossal motoneurons needs to include excitatory and inhibitory perihypoglossal interneurons that mediate noradrenergic and serotonergic drives to hypoglossal motoneurons. In the model, the state-dependent activation of the hypoglossal motoneurons was in qualitative agreement with in vivo data during simulated rapid eye movement (REM) and non-REM sleep. The model was applied to test the mechanisms of action of noradrenergic and serotonergic drugs during REM sleep as observed in vivo. We conclude that the proposed minimal neuronal circuit is sufficient to explain in vivo data and supports the hypothesis that perihypoglossal interneurons may mediate state-dependent monoaminergic drive to hypoglossal motoneurons. The population of the hypothesized perihypoglossal interneurons may serve as novel targets for pharmacological treatment of OSA. NEW & NOTEWORTHY In vivo studies suggest that during rapid eye movement sleep, withdrawal of noradrenergic and serotonergic drives critically contributes to depression of hypoglossal motoneurons (HMs), which innervate the tongue muscles. By means of a biophysical model, which is consistent with a broad range of empirical data, we demonstrate that the neuronal network controlling the excitability of HMs needs to include excitatory and inhibitory interneurons that mediate noradrenergic and serotonergic drives to HMs.
- Published
- 2018
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25. Loss of NAMPT in aging retinal pigment epithelium reduces NAD + availability and promotes cellular senescence.
- Author
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Jadeja RN, Powell FL, Jones MA, Fuller J, Joseph E, Thounaojam MC, Bartoli M, and Martin PM
- Subjects
- Acrylamides pharmacology, Animals, Cells, Cultured, Epithelial Cells, Gene Expression Regulation drug effects, Humans, Male, Mice, Nicotinamide Mononucleotide pharmacology, Piperidines pharmacology, Reverse Transcriptase Polymerase Chain Reaction, Aging physiology, Cytokines metabolism, NAD metabolism, Nicotinamide Phosphoribosyltransferase metabolism, Retinal Pigment Epithelium
- Abstract
Retinal pigment epithelium (RPE) performs numerous functions critical to retinal health and visual function. RPE senescence is a hallmark of aging and degenerative retinal disease development. Here, we evaluated the temporal expression of key nicotinamide adenine dinucleotide (NAD
+ )-biosynthetic genes and associated levels of NAD+ , a principal regulator of energy metabolism and cellular fate, in mouse RPE. NAD+ levels declined with age and correlated directly with decreased nicotinamide phosphoribosyltransferase (NAMPT) expression, increased expression of senescence markers (p16INK4a , p21Waf/Cip1 , ApoJ, CTGF and β-galactosidase) and significant reductions in SIRT1 expression and activity. We simulated in vitro the age-dependent decline in NAD+ and the related increase in RPE senescence in human (ARPE-19) and mouse primary RPE using the NAMPT inhibitor FK866 and demonstrated the positive impact of NAD+ -enhancing therapies on RPE cell viability. This, we confirmed in vivo in the RPE of mice injected sub-retinally with FK866 in the presence or absence of nicotinamide mononucleotide . Our data confirm the importance of NAD+ to RPE cell biology normally and in aging and demonstrate the potential utility of therapies targeting NAMPT and NAD+ biosynthesis to prevent or alleviate consequences of RPE senescence in aging and/or degenerative retinal diseases in which RPE dysfunction is a crucial element.- Published
- 2018
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26. Adaptive Servoventilation as Treatment for Central Sleep Apnea Due to High-Altitude Periodic Breathing in Nonacclimatized Healthy Individuals.
- Author
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Orr JE, Heinrich EC, Djokic M, Gilbertson D, Deyoung PN, Anza-Ramirez C, Villafuerte FC, Powell FL, Malhotra A, and Simonson T
- Subjects
- Acclimatization physiology, Adult, Female, Healthy Volunteers, Humans, Male, Middle Aged, Oximetry, Oxygen administration & dosage, Oxygen analysis, Polysomnography, Respiration, Sleep Apnea, Central etiology, Sleep Apnea, Central physiopathology, Treatment Outcome, Altitude, Interactive Ventilatory Support methods, Respiration, Artificial methods, Sleep Apnea, Central therapy
- Abstract
Orr, Jeremy E., Erica C. Heinrich, Matea Djokic, Dillon Gilbertson, Pamela N. Deyoung, Cecilia Anza-Ramirez, Francisco C. Villafuerte, Frank L. Powell, Atul Malhotra, and Tatum Simonson. Adaptive servoventilation as treatment for central sleep apnea due to high-altitude periodic breathing in nonacclimatized healthy individuals. High Alt Med Biol. 19:178-184, 2018., Aims: Central sleep apnea (CSA) is common at high altitude, leading to desaturation and sleep disruption. We hypothesized that noninvasive ventilation using adaptive servoventilation (ASV) would be effective at stabilizing CSA at altitude. Supplemental oxygen was evaluated for comparison., Methods: Healthy subjects were brought from sea level to 3800 m and underwent polysomnography on three consecutive nights. Subjects underwent each condition-No treatment, ASV, and supplemental oxygen-in random order. The primary outcome was the effect of ASV on oxygen desaturation index (ODI). Secondary outcomes included oxygen saturation, arousals, symptoms, and comparison to supplemental oxygen., Results: Eighteen subjects underwent at least two treatment conditions. There was a significant difference in ODI across the three treatments. There was no statistical difference in ODI between no treatment and ASV (17.1 ± 4.2 vs. 10.7 ± 2.9 events/hour; p > 0.17) and no difference in saturation or arousal index. Compared with no treatment, oxygen improved the ODI (16.5 ± 4.5 events/hour vs. 0.5 ± 0.2 events/hour; p < 0.003), in addition to saturation and arousal index., Conclusions: We found that ASV was not clearly efficacious at controlling CSA in persons traveling to 3800 m, whereas supplemental oxygen resolved CSA. Adjustment in the ASV algorithm may improve efficacy. ASV may have utility in acclimatized persons or at more modest altitudes.
- Published
- 2018
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27. Protective effects of agonists of growth hormone-releasing hormone (GHRH) in early experimental diabetic retinopathy.
- Author
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Thounaojam MC, Powell FL, Patel S, Gutsaeva DR, Tawfik A, Smith SB, Nussbaum J, Block NL, Martin PM, Schally AV, and Bartoli M
- Subjects
- Animals, Anti-Inflammatory Agents therapeutic use, Cell Adhesion Molecules genetics, Cell Adhesion Molecules metabolism, Cytokines genetics, Cytokines metabolism, Diabetic Retinopathy metabolism, GA-Binding Protein Transcription Factor genetics, GA-Binding Protein Transcription Factor metabolism, Growth Hormone-Releasing Hormone antagonists & inhibitors, Humans, Male, Rats, Rats, Sprague-Dawley, Retina drug effects, Retina metabolism, Sermorelin pharmacology, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Anti-Inflammatory Agents pharmacology, Diabetic Retinopathy drug therapy, Growth Hormone-Releasing Hormone agonists, Sermorelin analogs & derivatives
- Abstract
The potential therapeutic effects of agonistic analogs of growth hormone-releasing hormone (GHRH) and their mechanism of action were investigated in diabetic retinopathy (DR). Streptozotocin-induced diabetic rats (STZ-rats) were treated with 15 μg/kg GHRH agonist, MR-409, or GHRH antagonist, MIA-602. At the end of treatment, morphological and biochemical analyses assessed the effects of these compounds on retinal neurovascular injury induced by hyperglycemia. The expression levels of GHRH and its receptor (GHRH-R) measured by qPCR and Western blotting were significantly down-regulated in retinas of STZ-rats and in human diabetic retinas (postmortem) compared with their respective controls. Treatment of STZ-rats with the GHRH agonist, MR-409, prevented retinal morphological alteration induced by hyperglycemia, particularly preserving survival of retinal ganglion cells. The reverse, using the GHRH antagonist, MIA-602, resulted in worsening of retinal morphology and a significant alteration of the outer retinal layer. Explaining these results, we have found that MR-409 exerted antioxidant and anti-inflammatory effects in retinas of the treated rats, as shown by up-regulation of NRF-2-dependent gene expression and down-regulation of proinflammatory cytokines and adhesion molecules. MR-409 also significantly down-regulated the expression of vascular endothelial growth factor while increasing that of pigment epithelium-derived factor in diabetic retinas. These effects correlated with decreased vascular permeability. In summary, our findings suggest a neurovascular protective effect of GHRH analogs during the early stage of diabetic retinopathy through their antioxidant and anti-inflammatory properties., Competing Interests: Conflict of interest statement: N.L.B. owns equity in Biscayne Pharmaceuticals. A.V.S. is a coinventor on the patent for GHRH agonist, assigned to the University of Miami and the Veterans Affairs Medical Center, Miami, FL. However, the investigation of the effects of GHRH agonist MR-409 was an academic endeavor without any commercial interests. The other authors declare no conflict of interest., (Copyright © 2017 the Author(s). Published by PNAS.)
- Published
- 2017
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28. Evidence from high-altitude acclimatization for an integrated cerebrovascular and ventilatory hypercapnic response but different responses to hypoxia.
- Author
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Smith ZM, Krizay E, Sá RC, Li ET, Scadeng M, Powell FL Jr, and Dubowitz DJ
- Subjects
- Acclimatization, Adult, Altitude Sickness physiopathology, Carbon Dioxide blood, Female, Humans, Male, Oxygen blood, Respiration, Young Adult, Altitude, Cerebrovascular Circulation, Hypercapnia physiopathology, Hypoxia physiopathology
- Abstract
Ventilation and cerebral blood flow (CBF) are both sensitive to hypoxia and hypercapnia. To compare chemosensitivity in these two systems, we made simultaneous measurements of ventilatory and cerebrovascular responses to hypoxia and hypercapnia in 35 normal human subjects before and after acclimatization to hypoxia. Ventilation and CBF were measured during stepwise changes in isocapnic hypoxia and iso-oxic hypercapnia. We used MRI to quantify actual cerebral perfusion. Measurements were repeated after 2 days of acclimatization to hypoxia at 3,800 m altitude (partial pressure of inspired O
2 = 90 Torr) to compare plasticity in the chemosensitivity of these two systems. Potential effects of hypoxic and hypercapnic responses on acute mountain sickness (AMS) were assessed also. The pattern of CBF and ventilatory responses to hypercapnia were almost identical. CO2 responses were augmented to a similar degree in both systems by concomitant acute hypoxia or acclimatization to sustained hypoxia. Conversely, the pattern of CBF and ventilatory responses to hypoxia were markedly different. Ventilation showed the well-known increase with acute hypoxia and a progressive decline in absolute value over 25 min of sustained hypoxia. With acclimatization to hypoxia for 2 days, the absolute values of ventilation and O2 sensitivity increased. By contrast, O2 sensitivity of CBF or its absolute value did not change during sustained hypoxia for up to 2 days. The results suggest a common or integrated control mechanism for CBF and ventilation by CO2 but different mechanisms of O2 sensitivity and plasticity between the systems. Ventilatory and cerebrovascular responses were the same for all subjects irrespective of AMS symptoms. NEW & NOTEWORTHY Ventilatory and cerebrovascular hypercapnic response patterns show similar plasticity in CO2 sensitivity following hypoxic acclimatization, suggesting an integrated control mechanism. Conversely, ventilatory and cerebrovascular hypoxic responses differ. Ventilation initially increases but adapts with prolonged hypoxia (hypoxic ventilatory decline), and ventilatory sensitivity increases following acclimatization. In contrast, cerebral blood flow hypoxic sensitivity remains constant over a range of hypoxic stimuli, with no cerebrovascular acclimatization to sustained hypoxia, suggesting different mechanisms for O2 sensitivity in the two systems.- Published
- 2017
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29. STAT3-mediated activation of miR-21 is involved in down-regulation of TIMP3 and neovascularization in the ischemic retina.
- Author
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Gutsaeva DR, Thounaojam M, Rajpurohit S, Powell FL, Martin PM, Goei S, Duncan M, and Bartoli M
- Abstract
Retinal neovascularization (RNV) is a sight threatening complication of ischemic retinopathies with limited therapeutic options. The transcription factor signal transducer and activator of transcription 3 (STAT3) has been shown to play a crucial role in promoting RNV. However, manipulating of STAT3 activity can cause significant adverse side effects due to its neurotrophic properties. In this study, we identified microRNA-21 (miR-21) as a downstream effector of STAT3 activity in the ischemic retinas and determined its role in promoting RNV through inhibition of its molecular target, the tissue inhibitor of matrix metalloproteinases 3 (TIMP3). Using human retinal endothelial cells (HREC) exposed to hypoxia and a mouse model of oxygen-induced retinopathy (OIR), we found that TIMP3 expression was significantly decreased at both mRNA and protein levels and this paralleled the activation of STAT3 and up-regulation of miR-21 . Moreover, TIMP3 expression was restored by knockdown of STAT3 or blocking of miR-21 in HREC, thus, confirming TIMP3 as a downstream target of STAT3/ miR-21 pathway. Finally, in a mouse model of OIR, blockade of miR-21 by a specific antisense ( a.miR-21 ), halted RNV and this effect was associated with rescuing of TIMP3 expression. Our data show that miR-21 mediates STAT3 pro-angiogenic effects in the ischemic retina, thus suggesting its blockade as a potential therapy to prevent/halt RNV., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.
- Published
- 2017
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30. Transcriptomic analysis identifies a role of PI3K-Akt signalling in the responses of skeletal muscle to acute hypoxia in vivo.
- Author
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Gan Z, Powell FL, Zambon AC, Buchholz KS, Fu Z, Ocorr K, Bodmer R, Moya EA, Stowe JC, Haddad GG, and McCulloch AD
- Subjects
- Animals, Gene Expression Profiling, Gene Expression Regulation, Hypoxia metabolism, Male, Mice, Inbred C57BL, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, RNA, Messenger metabolism, Signal Transduction, Hypoxia genetics, Muscle, Skeletal metabolism, Phosphatidylinositol 3-Kinases genetics
- Abstract
Key Points: Changes in gene expression that occur within hours of exposure to hypoxia in in vivo skeletal muscles remain unexplored. Two hours of hypoxia caused significant down-regulation of extracellular matrix genes followed by a shift at 6 h to altered expression of genes associated with the nuclear lumen while respiratory and blood gases were stabilized. Enrichment analysis of mRNAs classified by stability rates suggests an attenuation of post-transcriptional regulation within hours of hypoxic exposure, where PI3K-Akt signalling was suggested to have a nodal role by pathway analysis. Experimental measurements and bioinformatic analyses suggested that the dephosphorylation of Akt after 2 h of hypoxic exposure might deactivate RNA-binding protein BRF1, hence resulting in the selective degradation of mRNAs., Abstract: The effects of acute hypoxia have been widely studied, but there are few studies of transcriptional responses to hours of hypoxia in vivo, especially in hypoxia-tolerant tissues like skeletal muscles. We used RNA-seq to analyse gene expression in plantaris muscles while monitoring respiration, arterial blood gases, and blood glucose in mice exposed to 8% O
2 for 2 or 6 h. Rapid decreases in blood gases and a slower reduction in blood glucose suggest stress, which was accompanied by widespread changes in gene expression. Early down-regulation of genes associated with the extracellular matrix was followed by a shift to genes associated with the nuclear lumen. Most of the early down-regulated genes had mRNA half-lives longer than 2 h, suggesting a role for post-transcriptional regulation. These transcriptional changes were enriched in signalling pathways in which the PI3K-Akt signalling pathway was identified as a hub. Our analyses indicated that gene targets of PI3K-Akt but not HIF were enriched in early transcriptional responses to hypoxia. Among the PI3K-Akt targets, 75% could be explained by a deactivation of adenylate-uridylate-rich element (ARE)-binding protein BRF1, a target of PI3K-Akt. Consistent decreases in the phosphorylation of Akt and BRF1 were experimentally confirmed following 2 h of hypoxia. These results suggest that the PI3K-Akt signalling pathway might play a role in responses induced by acute hypoxia in skeletal muscles, partially through the dephosphorylation of ARE-binding protein BRF1., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)- Published
- 2017
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31. Giants in Chest Medicine: John B. West, MD, PhD, DSc.
- Author
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Powell FL
- Subjects
- History, 20th Century, Humans, United States, Biomedical Research history, Lung Diseases history, Pulmonary Medicine history
- Published
- 2017
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32. Minocycline blocks glial cell activation and ventilatory acclimatization to hypoxia.
- Author
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Stokes JA, Arbogast TE, Moya EA, Fu Z, and Powell FL
- Subjects
- Acclimatization drug effects, Analysis of Variance, Animals, Glial Fibrillary Acidic Protein metabolism, Male, Plethysmography, Rats, Rats, Sprague-Dawley, Solitary Nucleus cytology, Anti-Bacterial Agents pharmacology, Hypoxia pathology, Minocycline pharmacology, Neuroglia drug effects, Respiration drug effects, Respiratory Center pathology
- Abstract
Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation, which persists upon return to normoxia and involves plasticity in both central nervous system respiratory centers and peripheral chemoreceptors. We investigated the role of glial cells in VAH in male Sprague-Dawley rats using minocycline, an antibiotic that inhibits microglia activation and has anti-inflammatory properties, and barometric pressure plethysmography to measure ventilation. Rats received either minocycline (45mg/kg ip daily) or saline beginning 1 day before and during 7 days of chronic hypoxia (CH, Pi
O = 70 Torr). Minocycline had no effect on normoxic control rats or the hypercapnic ventilatory response in CH rats, but minocycline significantly ( P < 0.001) decreased ventilation during acute hypoxia in CH rats. However, minocycline administration during only the last 3 days of CH did not reverse VAH. Microglia and astrocyte activation in the nucleus tractus solitarius was quantified from 30 min to 7 days of CH. Microglia showed an active morphology (shorter and fewer branches) after 1 h of hypoxia and returned to the control state (longer filaments and extensive branching) after 4 h of CH. Astrocytes increased glial fibrillary acidic protein antibody immunofluorescent intensity, indicating activation, at both 4 and 24 h of CH. Minocycline had no effect on glia in normoxia but significantly decreased microglia activation at 1 h of CH and astrocyte activation at 24 h of CH. These results support a role for glial cells, providing an early signal for the induction but not maintenance of neural plasticity underlying ventilatory acclimatization to hypoxia. NEW & NOTEWORTHY The signals for neural plasticity in medullary respiratory centers underlying ventilatory acclimatization to chronic hypoxia are unknown. We show that chronic hypoxia activates microglia and subsequently astrocytes. Minocycline, an antibiotic that blocks microglial activation and has anti-inflammatory properties, also blocks astrocyte activation in respiratory centers during chronic hypoxia and ventilatory acclimatization. However, minocycline cannot reverse ventilatory acclimatization after it is established. Hence, glial cells may provide signals that initiate but do not sustain ventilatory acclimatization., (Copyright © 2017 the American Physiological Society.)2 - Published
- 2017
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33. Interactome Mapping Guided by Tissue-Specific Phosphorylation in Age-Related Macular Degeneration.
- Author
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Sripathi SR, He W, Prigge CL, Sylvester O, Um JY, Powell FL, Neksumi M, Bernstein PS, Choo DW, Bartoli M, Gutsaeva DR, and Jahng WJ
- Abstract
The current study aims to determine the molecular mechanisms of age-related macular degeneration (AMD) using the phosphorylation network. Specifically, we examined novel biomarkers for oxidative stress by protein interaction mapping using in vitro and in vivo models that mimic the complex and progressive characteristics of AMD. We hypothesized that the early apoptotic reactions could be initiated by protein phosphorylation in region-dependent (peripheral retina vs. macular) and tissue-dependent (retinal pigment epithelium vs. retina) manner under chronic oxidative stress. The analysis of protein interactome and oxidative biomarkers showed the presence of tissue- and region-specific post-translational mechanisms that contribute to AMD progression and suggested new therapeutic targets that include ubiquitin, erythropoietin, vitronectin, MMP2, crystalline, nitric oxide, and prohibitin. Phosphorylation of specific target proteins in RPE cells is a central regulatory mechanism as a survival tool under chronic oxidative imbalance. The current interactome map demonstrates a positive correlation between oxidative stress-mediated phosphorylation and AMD progression and provides a basis for understanding oxidative stress-induced cytoskeletal changes and the mechanism of aggregate formation induced by protein phosphorylation. This information could provide an effective therapeutic approach to treat age-related neurodegeneration., Competing Interests: COMPETING INTERESTS None
- Published
- 2017
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34. The impact of inflammation on respiratory plasticity.
- Author
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Hocker AD, Stokes JA, Powell FL, and Huxtable AG
- Subjects
- Animals, Humans, Hypoxia physiopathology, Inflammation complications, Inflammation pathology, Neuronal Plasticity physiology, Respiratory System physiopathology
- Abstract
Breathing is a vital homeostatic behavior and must be precisely regulated throughout life. Clinical conditions commonly associated with inflammation, undermine respiratory function may involve plasticity in respiratory control circuits to compensate and maintain adequate ventilation. Alternatively, other clinical conditions may evoke maladaptive plasticity. Yet, we have only recently begun to understand the effects of inflammation on respiratory plasticity. Here, we review some of common models used to investigate the effects of inflammation and discuss the impact of inflammation on nociception, chemosensory plasticity, medullary respiratory centers, motor plasticity in motor neurons and respiratory frequency, and adaptation to high altitude. We provide new data suggesting glial cells contribute to CNS inflammatory gene expression after 24h of sustained hypoxia and inflammation induced by 8h of intermittent hypoxia inhibits long-term facilitation of respiratory frequency. We also discuss how inflammation can have opposite effects on the capacity for plasticity, whereby it is necessary for increases in the hypoxic ventilatory response with sustained hypoxia, but inhibits phrenic long term facilitation after intermittent hypoxia. This review highlights gaps in our knowledge about the effects of inflammation on respiratory control (development, age, and sex differences). In summary, data to date suggest plasticity can be either adaptive or maladaptive and understanding how inflammation alters the respiratory system is crucial for development of better therapeutic interventions to promote breathing and for utilization of plasticity as a clinical treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2017
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35. Oral Monomethyl Fumarate Therapy Ameliorates Retinopathy in a Humanized Mouse Model of Sickle Cell Disease.
- Author
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Promsote W, Powell FL, Veean S, Thounaojam M, Markand S, Saul A, Gutsaeva D, Bartoli M, Smith SB, Ganapathy V, and Martin PM
- Subjects
- Administration, Oral, Anemia, Sickle Cell blood, Anemia, Sickle Cell diagnosis, Animals, Blood-Retinal Barrier metabolism, Blood-Retinal Barrier pathology, Carrier Proteins genetics, Carrier Proteins metabolism, DNA-Binding Proteins, Disease Models, Animal, Electroretinography, Gene Expression, Gene Expression Regulation, Humans, Intercellular Adhesion Molecule-1 genetics, Intercellular Adhesion Molecule-1 metabolism, Mice, NF-E2-Related Factor 2 metabolism, Neovascularization, Pathologic, Nuclear Proteins genetics, Nuclear Proteins metabolism, Oxidative Stress drug effects, Repressor Proteins, Retina drug effects, Retina metabolism, Retina pathology, Retinal Diseases drug therapy, Retinal Diseases metabolism, Retinal Neurons drug effects, Retinal Neurons metabolism, Retinal Neurons pathology, Retinal Pigment Epithelium drug effects, Retinal Pigment Epithelium metabolism, Retinal Pigment Epithelium pathology, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, gamma-Globulins genetics, gamma-Globulins metabolism, Anemia, Sickle Cell complications, Fumarates administration & dosage, Retinal Diseases etiology, Retinal Diseases pathology
- Abstract
Aims: Sickle retinopathy (SR) is a major cause of blindness in sickle cell disease (SCD). The genetic mutation responsible for SCD is known, however; oxidative stress and inflammation also figure prominently in the development and progression of pathology. Development of therapies for SR is hampered by the lack of (a) animal models that accurately recapitulate human SR and (b) strategies for noninvasive yet effective retinal drug delivery. This study addressed both issues by validating the Townes humanized SCD mouse as a model of SR and demonstrating the efficacy of oral administration of the antioxidant fumaric acid ester monomethyl fumarate (MMF) in the disease., Results: In vivo ophthalmic imaging, electroretinography, and postmortem histological RNA and protein analyses were used to monitor retinal health and function in normal (HbAA) and sickle (HbSS) hemoglobin-producing mice over a one-year period and in additional HbAA and HbSS mice treated with MMF (15 mg/ml) for 5 months. Functional and morphological abnormalities and molecular hallmarks of oxidative stress/inflammation were evident early in HbSS retinas and increased in number and severity with age. Treatment with MMF, a known inducer of Nrf2, induced γ-globin expression and fetal hemoglobin production, improved hematological profiles, and ameliorated SR-related pathology. Innovation and Conclusion: United States Food and Drug Administration-approved formulations in which MMF is the primary bioactive ingredient are currently available to treat multiple sclerosis; such drugs may be effective for treatment of ocular and systemic complications of SCD, and given the pleiotropic effects, other nonsickle-related diseases in which oxidative stress, inflammation, and retinal vascular pathology figure prominently. Antioxid. Redox Signal. 25, 921-935., Competing Interests: Author Disclosure Statement V.G. and P.M.M. are coinventors of US20140171504 A1 patent titled “Methods of treating SCD and related disorders using fumaric acid esters.” The remaining authors have no disclosures or competing financial interests to report.
- Published
- 2016
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36. Dual Anti-Inflammatory and Anti-Angiogenic Action of miR-15a in Diabetic Retinopathy.
- Author
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Wang Q, Navitskaya S, Chakravarthy H, Huang C, Kady N, Lydic TA, Chen YE, Yin KJ, Powell FL, Martin PM, Grant MB, and Busik JV
- Subjects
- 3' Untranslated Regions, Animals, Cell Movement genetics, Cells, Cultured, Ceramides biosynthesis, Diabetes Mellitus, Experimental, Diabetic Retinopathy metabolism, Disease Models, Animal, Endothelial Cells, Gene Expression Profiling, Gene Expression Regulation, Humans, Male, Mice, RNA Interference, Rats, Retina metabolism, Retinal Pigment Epithelium cytology, Retinal Pigment Epithelium metabolism, Retinal Vessels, Sphingomyelin Phosphodiesterase genetics, Sphingomyelin Phosphodiesterase metabolism, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Diabetic Retinopathy genetics, Diabetic Retinopathy pathology, MicroRNAs genetics, Neovascularization, Pathologic genetics
- Abstract
Activation of pro-inflammatory and pro-angiogenic pathways in the retina and the bone marrow contributes to pathogenesis of diabetic retinopathy. We identified miR-15a as key regulator of both pro-inflammatory and pro-angiogenic pathways through direct binding and inhibition of the central enzyme in the sphingolipid metabolism, ASM, and the pro-angiogenic growth factor, VEGF-A. miR-15a was downregulated in diabetic retina and bone marrow cells. Over-expression of miR-15a downregulated, and inhibition of miR-15a upregulated ASM and VEGF-A expression in retinal cells. In addition to retinal effects, migration and retinal vascular repair function was impaired in miR-15a inhibitor-treated circulating angiogenic cells (CAC). Diabetic mice overexpressing miR-15a under Tie-2 promoter had normalized retinal permeability compared to wild type littermates. Importantly, miR-15a overexpression led to modulation toward nondiabetic levels, rather than complete inhibition of ASM and VEGF-A providing therapeutic effect without detrimental consequences of ASM and VEGF-A deficiencies., (Copyright © 2016 Forschungsgesellschaft für Arbeitsphysiologie und Arbeitschutz e.V. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
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37. Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis.
- Author
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Pamenter ME and Powell FL
- Subjects
- Chemoreceptor Cells metabolism, Humans, Neuronal Plasticity physiology, Neurotransmitter Agents physiology, Reflex physiology, Respiratory Mechanics physiology, Hypoxia physiopathology, Pulmonary Ventilation physiology
- Abstract
Ventilatory responses to hypoxia vary widely depending on the pattern and length of hypoxic exposure. Acute, prolonged, or intermittent hypoxic episodes can increase or decrease breathing for seconds to years, both during the hypoxic stimulus, and also after its removal. These myriad effects are the result of a complicated web of molecular interactions that underlie plasticity in the respiratory control reflex circuits and ultimately control the physiology of breathing in hypoxia. Since the time domains of the physiological hypoxic ventilatory response (HVR) were identified, considerable research effort has gone toward elucidating the underlying molecular mechanisms that mediate these varied responses. This research has begun to describe complicated and plastic interactions in the relay circuits between the peripheral chemoreceptors and the ventilatory control circuits within the central nervous system. Intriguingly, many of these molecular pathways seem to share key components between the different time domains, suggesting that varied physiological HVRs are the result of specific modifications to overlapping pathways. This review highlights what has been discovered regarding the cell and molecular level control of the time domains of the HVR, and highlights key areas where further research is required. Understanding the molecular control of ventilation in hypoxia has important implications for basic physiology and is emerging as an important component of several clinical fields. © 2016 American Physiological Society. Compr Physiol 6:1345-1385, 2016., (Copyright © 2016 John Wiley & Sons, Inc.)
- Published
- 2016
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38. Ibuprofen Blunts Ventilatory Acclimatization to Sustained Hypoxia in Humans.
- Author
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Basaran KE, Villongco M, Ho B, Ellis E, Zarndt R, Antonova J, Hopkins SR, and Powell FL
- Subjects
- Adolescent, Adult, Altitude, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Carotid Body physiopathology, Chronic Disease, Cross-Over Studies, Double-Blind Method, Female, Humans, Ibuprofen pharmacology, Male, Oxygen blood, Partial Pressure, Respiratory Center physiopathology, Young Adult, Acclimatization drug effects, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Carotid Body drug effects, Chemoreceptor Cells drug effects, Hypoxia physiopathology, Ibuprofen adverse effects, Neuronal Plasticity drug effects, Respiration drug effects, Respiratory Center drug effects
- Abstract
Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation and the hypoxic ventilatory response (HVR) that involves neural plasticity in both carotid body chemoreceptors and brainstem respiratory centers. The mechanisms of such plasticity are not completely understood but recent animal studies show it can be blocked by administering ibuprofen, a nonsteroidal anti-inflammatory drug, during chronic hypoxia. We tested the hypothesis that ibuprofen would also block the increase in HVR with chronic hypoxia in humans in 15 healthy men and women using a double-blind, placebo controlled, cross-over trial. The isocapnic HVR was measured with standard methods in subjects treated with ibuprofen (400 mg every 8 hrs) or placebo for 48 hours at sea level and 48 hours at high altitude (3,800 m). Subjects returned to sea level for at least 30 days prior to repeating the protocol with the opposite treatment. Ibuprofen significantly decreased the HVR after acclimatization to high altitude compared to placebo but it did not affect ventilation or arterial O2 saturation breathing ambient air at high altitude. Hence, compensatory responses prevent hypoventilation with decreased isocapnic ventilatory O2-sensitivity from ibuprofen at this altitude. The effect of ibuprofen to decrease the HVR in humans provides the first experimental evidence that a signaling mechanism described for ventilatory acclimatization to hypoxia in animal models also occurs in people. This establishes a foundation for the future experiments to test the potential role of different mechanisms for neural plasticity and ventilatory acclimatization in humans with chronic hypoxemia from lung disease.
- Published
- 2016
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39. A Protocol to Collect Specific Mouse Skeletal Muscles for Metabolomics Studies.
- Author
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Gan Z, Fu Z, Stowe JC, Powell FL, and McCulloch AD
- Subjects
- Animals, Lactic Acid, Mice, Metabolomics methods, Muscle, Skeletal metabolism
- Abstract
Due to the highly sensitive nature of metabolic states, the quality of metabolomics data depends on the suitability of the experimental procedure. Metabolism could be affected by factors such as the method of euthanasia of the animals and the sample collection procedures. The effects of these factors on metabolites are tissue-specific. Thus, it is important to select proper methods to sacrifice the animal and appropriate procedures for collecting samples specific to the tissue of interest. Here, we present our protocol to collect specific mouse skeletal muscles with different fiber types for metabolomics studies. We also provide a protocol to measure lactate levels in tissue samples as a way to estimate the metabolic state in collected samples.
- Published
- 2016
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40. Cardiac responses to hypoxia and reoxygenation in Drosophila.
- Author
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Zarndt R, Piloto S, Powell FL, Haddad GG, Bodmer R, and Ocorr K
- Subjects
- Adaptation, Physiological, Animals, Cardiac Output, Collagen metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Drosophila Proteins genetics, Drosophila Proteins metabolism, Drosophila melanogaster genetics, Female, Fibrosis, Genotype, Heart Rate, Hypoxia pathology, Hypoxia physiopathology, Mutation, Myocardial Contraction, Myocardium pathology, Phenotype, Recovery of Function, Time Factors, Drosophila melanogaster metabolism, Hemodynamics, Hypoxia metabolism, Myocardium metabolism, Oxygen metabolism
- Abstract
An adequate supply of oxygen is important for the survival of all tissues, but it is especially critical for tissues with high-energy demands, such as the heart. Insufficient tissue oxygenation occurs under a variety of conditions, including high altitude, embryonic and fetal development, inflammation, and thrombotic diseases, often affecting multiple organ systems. Responses and adaptations of the heart to hypoxia are of particular relevance in human cardiovascular and pulmonary diseases, in which the effects of hypoxic exposure can range in severity from transient to long-lasting. This study uses the genetic model system Drosophila to investigate cardiac responses to acute (30 min), sustained (18 h), and chronic (3 wk) hypoxia with reoxygenation. Whereas hearts from wild-type flies recovered quickly after acute hypoxia, exposure to sustained or chronic hypoxia significantly compromised heart function upon reoxygenation. Hearts from flies with mutations in sima, the Drosophila homolog of the hypoxia-inducible factor alpha subunit (HIF-α), exhibited exaggerated reductions in cardiac output in response to hypoxia. Heart function in hypoxia-selected flies, selected over many generations for survival in a low-oxygen environment, revealed reduced cardiac output in terms of decreased heart rate and fractional shortening compared with their normoxia controls. Hypoxia-selected flies also had smaller hearts, myofibrillar disorganization, and increased extracellular collagen deposition, consistent with the observed reductions in contractility. This study indicates that longer-duration hypoxic insults exert deleterious effects on heart function that are mediated, in part, by sima and advances Drosophila models for the genetic analysis of cardiac-specific responses to hypoxia and reoxygenation., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
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41. Notch Activation of Ca(2+) Signaling in the Development of Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension.
- Author
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Smith KA, Voiriot G, Tang H, Fraidenburg DR, Song S, Yamamura H, Yamamura A, Guo Q, Wan J, Pohl NM, Tauseef M, Bodmer R, Ocorr K, Thistlethwaite PA, Haddad GG, Powell FL, Makino A, Mehta D, and Yuan JX
- Subjects
- Animals, Calcium-Binding Proteins metabolism, Cell Hypoxia, Cells, Cultured, Humans, Hypertension, Pulmonary physiopathology, Intercellular Signaling Peptides and Proteins metabolism, Male, Membrane Proteins metabolism, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular physiopathology, Myocytes, Smooth Muscle metabolism, Pulmonary Artery metabolism, Pulmonary Artery physiopathology, Serrate-Jagged Proteins, TRPC Cation Channels antagonists & inhibitors, TRPC Cation Channels genetics, TRPC Cation Channels metabolism, TRPC6 Cation Channel, Calcium Signaling, Hypertension, Pulmonary metabolism, Receptor, Notch1 metabolism, Vasoconstriction
- Abstract
Hypoxic pulmonary vasoconstriction (HPV) is an important physiological response that optimizes the ventilation/perfusion ratio. Chronic hypoxia causes vascular remodeling, which is central to the pathogenesis of hypoxia-induced pulmonary hypertension (HPH). We have previously shown that Notch3 is up-regulated in HPH and that activation of Notch signaling enhances store-operated Ca(2+) entry (SOCE), an important mechanism that contributes to pulmonary arterial smooth muscle cell (PASMC) proliferation and contraction. Here, we investigate the role of Notch signaling in HPV and hypoxia-induced enhancement of SOCE. We examined SOCE in human PASMCs exposed to hypoxia and pulmonary arterial pressure in mice using the isolated perfused/ventilated lung method. Wild-type and canonical transient receptor potential (TRPC) 6(-/-) mice were exposed to chronic hypoxia to induce HPH. Inhibition of Notch signaling with a γ-secretase inhibitor attenuates hypoxia-enhanced SOCE in PASMCs and hypoxia-induced increase in pulmonary arterial pressure. Our results demonstrate that hypoxia activates Notch signaling and up-regulates TRPC6 channels. Additionally, treatment with a Notch ligand can mimic hypoxic responses. Finally, inhibition of TRPC6, either pharmacologically or genetically, attenuates HPV, hypoxia-enhanced SOCE, and the development of HPH. These results demonstrate that hypoxia-induced activation of Notch signaling mediates HPV and the development of HPH via functional activation and up-regulation of TRPC6 channels. Understanding the molecular mechanisms that regulate cytosolic free Ca(2+) concentration and PASMC proliferation is critical to elucidation of the pathogenesis of HPH. Targeting Notch regulation of TRPC6 will be beneficial in the development of novel therapies for pulmonary hypertension associated with hypoxia.
- Published
- 2015
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42. High Prevalence of Obstructive Sleep Apnea in Patients with Moderate to Severe Chronic Obstructive Pulmonary Disease.
- Author
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Soler X, Gaio E, Powell FL, Ramsdell JW, Loredo JS, Malhotra A, and Ries AL
- Subjects
- Aged, Female, Humans, Linear Models, Male, Middle Aged, Multivariate Analysis, Oxygen therapeutic use, Prospective Studies, Quality of Life, Severity of Illness Index, Surveys and Questionnaires, Polysomnography methods, Pulmonary Disease, Chronic Obstructive complications, Sleep Apnea, Obstructive complications, Sleep Apnea, Obstructive epidemiology
- Abstract
Rationale: When obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) coexist in the so-called "overlap" syndrome, a high risk for mortality and morbidity has been reported. There is controversy about the prevalence of OSA in people affected by COPD., Objectives: The purpose of this study was to investigate objective meaures of sleep-disordered breathing in patients with moderate to severe COPD to test the hypothesis that COPD is associated with an increased prevalence of OSA., Methods: Fifty-four patients (54% men) with moderate to severe COPD were enrolled prospectively (mean ± SD, FEV1 = 42.8 ± 19.8% predicted, and FEV1/FVC = 42.3 ± 13.1). Twenty patients (37%) were on supplemental oxygen at baseline. Exercise tolerance; questionnaires related to symptoms, sleep, and quality of life; and home polysomnography were obtained., Measurements and Main Results: Forty-four patients had full polysomnography suitable for analysis. OSA (apnea-hypopnea index > 5/h) was present in 29 subjects (65.9%). Sleep efficiency was poor in 45% of subjects., Conclusions: OSA is highly prevalent in patients with moderate to severe COPD referred to pulmonary rehabilitation. Sleep quality is also poor among this selected group. These patients have greater-than-expected sleep-disordered breathing, which could be an important contributory factor to morbidity and mortality. Pulmonary rehabilitation programs should consider including a sleep assessment in patients with moderate to severe COPD and interventions when indicated to help reduce the impact of OSA in COPD.
- Published
- 2015
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43. No evidence of a role for neuronal nitric oxide synthase in the nucleus tractus solitarius in ventilatory responses to acute or chronic hypoxia in awake rats.
- Author
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Pamenter ME, Go A, Fu Z, and Powell FL
- Subjects
- Acclimatization physiology, Animals, Central Nervous System drug effects, Central Nervous System metabolism, Central Nervous System physiology, Citrulline analogs & derivatives, Citrulline pharmacology, Male, NG-Nitroarginine Methyl Ester pharmacology, Pulmonary Ventilation drug effects, Rats, Rats, Sprague-Dawley, Reflex drug effects, Reflex physiology, Respiration drug effects, Solitary Nucleus drug effects, Thiourea analogs & derivatives, Thiourea pharmacology, Ventilation methods, Wakefulness drug effects, Hypoxia metabolism, Hypoxia physiopathology, Nitric Oxide Synthase Type I metabolism, Pulmonary Ventilation physiology, Solitary Nucleus metabolism, Solitary Nucleus physiology, Wakefulness physiology
- Abstract
When exposed to a hypoxic environment, the body's first response is a reflex increase in ventilation, termed the hypoxic ventilatory response (HVR). With chronic sustained hypoxia (CSH), such as during acclimatization to high altitude, an additional time-dependent increase in ventilation occurs, which increases the HVR and is termed ventilatory acclimatization to hypoxia (VAH). This secondary increase persists after exposure to CSH and involves plasticity within the circuits in the central nervous system that control breathing. The mechanisms of HVR plasticity are currently poorly understood. We hypothesized that changes in neuronal nitric oxide synthase (nNOS) activity or expression in the nucleus tractus solitarius contribute to this plasticity and underlie VAH in rats. To test this, we treated rats held in normoxia or 10% O2 (CSH, PIO2 = 70 Torr) for 7-9 days and measured ventilation in conscious, unrestrained animals before and after microinjecting the general NOS antagonist L-NG-Nitroarginine methyl ester into the nucleus tractus solitarius (NTS) or systemically injecting the nNOS-specific antagonist S-methyl-l-thiocitrulline. Localization of injection sites in the NTS was confirmed by histology following the experiment. We found that 1) neither NTS-specific nor systemic nNOS antagonism had any effect on hypoxia-mediated changes in breathing or metabolism (P > 0.05), but 2) nNOS protein expression was increased in the middle and caudal NTS by CSH. A persistent HVR after nNOS blockade in the NTS contrasts with results in awake mice, and our findings do not support the hypotheses that nNOS in the NTS contribute to the HVR or VAH in awake rats., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
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44. The effect of combined glutamate receptor blockade in the NTS on the hypoxic ventilatory response in awake rats differs from the effect of individual glutamate receptor blockade.
- Author
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Pamenter ME, Nguyen J, Carr JA, and Powell FL
- Abstract
Ventilatory acclimatization to hypoxia (VAH) increases the hypoxic ventilatory response (HVR) and causes persistent hyperventilation when normoxia is restored, which is consistent with the occurrence of synaptic plasticity in acclimatized animals. Recently, we demonstrated that antagonism of individual glutamate receptor types (GluRs) within the nucleus tractus solitarii (NTS) modifies this plasticity and VAH (J. Physiol. 592(8):1839-1856); however, the effects of combined GluR antagonism remain unknown in awake rats. To evaluate this, we exposed rats to room air or chronic sustained hypobaric hypoxia (CSH, PiO2 = 70 Torr) for 7-9 days. On the experimental day, we microinjected artificial cerebrospinal fluid (ACSF: sham) and then a "cocktail" of the GluR antagonists MK-801 and DNQX into the NTS. The location of injection sites in the NTS was confirmed by glutamate injections on a day before the experiment and with histology following the experiment. Ventilation was measured in awake, unrestrained rats breathing normoxia or acute hypoxia (10% O2) in 15-min intervals using barometric pressure plethysmography. In control (CON) rats, acute hypoxia increased ventilation; NTS microinjections of GluR antagonists, but not ACSF, significantly decreased ventilation and breathing frequency in acute hypoxia but not normoxia (P < 0.05). CSH increased ventilation in hypoxia and acute normoxia. In CSH-conditioned rats, GluR antagonists in the NTS significantly decreased ventilation in normoxia and breathing frequency in hypoxia. A persistent HVR after combined GluR blockade in the NTS contrasts with the effect of individual GluR blockade and also with results in anesthetized rats. Our findings support the hypotheses that GluRs in the NTS contribute to, but cannot completely explain, VAH in awake rats., (© 2014 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)
- Published
- 2014
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45. Activation of Notch signaling by short-term treatment with Jagged-1 enhances store-operated Ca(2+) entry in human pulmonary arterial smooth muscle cells.
- Author
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Yamamura H, Yamamura A, Ko EA, Pohl NM, Smith KA, Zeifman A, Powell FL, Thistlethwaite PA, and Yuan JX
- Subjects
- Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid Precursor Protein Secretases metabolism, Animals, Calcium Channels metabolism, Cells, Cultured, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Humans, Jagged-1 Protein, Male, Mice, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle metabolism, Pulmonary Artery drug effects, Pulmonary Artery metabolism, Receptors, Notch metabolism, Sarcoplasmic Reticulum drug effects, Sarcoplasmic Reticulum metabolism, Serrate-Jagged Proteins, Time Factors, Calcium Channel Agonists pharmacology, Calcium Channels drug effects, Calcium Signaling drug effects, Calcium-Binding Proteins pharmacology, Intercellular Signaling Peptides and Proteins pharmacology, Membrane Proteins pharmacology, Muscle, Smooth, Vascular drug effects, Myocytes, Smooth Muscle drug effects, Peptide Fragments pharmacology, Receptors, Notch agonists
- Abstract
Notch signaling plays a critical role in controlling proliferation and differentiation of pulmonary arterial smooth muscle cells (PASMC). Upregulated Notch ligands and Notch3 receptors in PASMC have been reported to promote the development of pulmonary vascular remodeling in patients with pulmonary arterial hypertension (PAH) and in animals with experimental pulmonary hypertension. Activation of Notch receptors by their ligands leads to the cleavage of the Notch intracellular domain (NICD) to the cytosol by γ-secretase; NICD then translocates into the nucleus to regulate gene transcription. In this study, we examined whether short-term activation of Notch functionally regulates store-operated Ca(2+) entry (SOCE) in human PASMC. Treatment of PASMC with the active fragment of human Jagged-1 protein (Jag-1) for 15-60 min significantly increased the amplitude of SOCE induced by passive deletion of Ca(2+) from the intracellular stores, the sarcoplasmic reticulum (SR). The Jag-1-induced enhancement of SOCE was time dependent: the amplitude was maximized at 30 min of treatment with Jag-1, which was closely correlated with the time course of Jag-1-mediated increase in NICD protein level. The scrambled peptide of Jag-1 active fragment had no effect on SOCE. Inhibition of γ-secretase by N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) significantly attenuated the Jag-1-induced augmentation of SOCE. In addition to the short-term effect, prolonged treatment of PASMC with Jag-1 for 48 h also markedly enhanced the amplitude of SOCE. These data demonstrate that short-term activation of Notch signaling enhances SOCE in PASMC; the NICD-mediated functional interaction with store-operated Ca(2+) channels (SOC) may be involved in the Jag-1-mediated enhancement of SOCE in human PASMC.
- Published
- 2014
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46. Glutamate receptors in the nucleus tractus solitarius contribute to ventilatory acclimatization to hypoxia in rat.
- Author
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Pamenter ME, Carr JA, Go A, Fu Z, Reid SG, and Powell FL
- Subjects
- Animals, Chemoreceptor Cells drug effects, Chemoreceptor Cells metabolism, Dizocilpine Maleate pharmacology, Excitatory Amino Acid Agonists pharmacology, Excitatory Amino Acid Antagonists pharmacology, Hypoxia physiopathology, Male, N-Methylaspartate pharmacology, Quinoxalines pharmacology, Rats, Rats, Sprague-Dawley, Reflex, Solitary Nucleus cytology, Solitary Nucleus metabolism, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid pharmacology, Acclimatization, Hypoxia metabolism, Pulmonary Ventilation, Receptors, Glutamate metabolism, Solitary Nucleus physiology
- Abstract
When exposed to a hypoxic environment the body's first response is a reflex increase in ventilation, termed the hypoxic ventilatory response (HVR). With chronic sustained hypoxia (CSH), such as during acclimatization to high altitude, an additional time-dependent increase in ventilation occurs, which increases the HVR. This secondary increase persists after exposure to CSH and involves plasticity within the circuits in the central nervous system that control breathing. Currently these mechanisms of HVR plasticity are unknown and we hypothesized that they involve glutamatergic synapses in the nucleus tractus solitarius (NTS), where afferent endings from arterial chemoreceptors terminate. To test this, we treated rats held in normoxia (CON) or 10% O2 (CSH) for 7 days and measured ventilation in conscious, unrestrained animals before and after microinjecting glutamate receptor agonists and antagonists into the NTS. In normoxia, AMPA increased ventilation 25% and 50% in CON and CSH, respectively, while NMDA doubled ventilation in both groups (P < 0.05). Specific AMPA and NMDA receptor antagonists (NBQX and MK801, respectively) abolished these effects. MK801 significantly decreased the HVR in CON rats, and completely blocked the acute HVR in CSH rats but had no effect on ventilation in normoxia. NBQX decreased ventilation whenever it was increased relative to normoxic controls; i.e. acute hypoxia in CON and CSH, and normoxia in CSH. These results support our hypothesis that glutamate receptors in the NTS contribute to plasticity in the HVR with CSH. The mechanism underlying this synaptic plasticity is probably glutamate receptor modification, as in CSH rats the expression of phosphorylated NR1 and GluR1 proteins in the NTS increased 35% and 70%, respectively, relative to that in CON rats.
- Published
- 2014
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47. Less is more: blunted responses to hypoxia revealed in sea-level Tibetans.
- Author
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Simonson TS and Powell FL
- Subjects
- Humans, Male, Acclimatization, Altitude, Asian People genetics, Basic Helix-Loop-Helix Transcription Factors genetics, Hypoxia genetics, Hypoxia-Inducible Factor-Proline Dioxygenases genetics, Selection, Genetic
- Published
- 2014
- Full Text
- View/download PDF
48. Role of chemoreception in cardiorespiratory acclimatization to, and deacclimatization from, hypoxia.
- Author
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Dempsey JA, Powell FL, Bisgard GE, Blain GM, Poulin MJ, and Smith CA
- Subjects
- Animals, Blood Pressure, Cardiovascular System innervation, Cardiovascular System physiopathology, Carotid Body physiopathology, Central Nervous System metabolism, Central Nervous System physiopathology, Humans, Hydrogen-Ion Concentration, Hypoxia cerebrospinal fluid, Hypoxia physiopathology, Lung innervation, Lung physiopathology, Oxygen cerebrospinal fluid, Sleep Apnea Syndromes blood, Sleep Apnea Syndromes cerebrospinal fluid, Sleep Apnea Syndromes physiopathology, Sympathetic Nervous System metabolism, Sympathetic Nervous System physiopathology, Time Factors, Vasoconstriction, Acclimatization, Altitude, Carotid Body metabolism, Hemodynamics, Hypoxia blood, Oxygen blood, Pulmonary Ventilation
- Abstract
During sojourn to high altitudes, progressive time-dependent increases occur in ventilation and in sympathetic nerve activity over several days, and these increases persist upon acute restoration of normoxia. We discuss evidence concerning potential mediators of these changes, including the following: 1) correction of alkalinity in cerebrospinal fluid; 2) increased sensitivity of carotid chemoreceptors; and 3) augmented translation of carotid chemoreceptor input (at the level of the central nervous system) into increased respiratory motor output via sensitization of hypoxic sensitive neurons in the central nervous system and/or an interdependence of central chemoreceptor responsiveness on peripheral chemoreceptor sensory input. The pros and cons of chemoreceptor sensitization and cardiorespiratory acclimatization to hypoxia and intermittent hypoxemia are also discussed in terms of their influences on arterial oxygenation, the work of breathing, sympathoexcitation, systemic blood pressure, and exercise performance. We propose that these adaptive processes may have negative implications for the cardiovascular health of patients with sleep apnea and perhaps even for athletes undergoing regimens of "sleep high-train low"!
- Published
- 2014
- Full Text
- View/download PDF
49. Substance P differentially modulates firing rate of solitary complex (SC) neurons from control and chronic hypoxia-adapted adult rats.
- Author
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Nichols NL, Powell FL, Dean JB, and Putnam RW
- Subjects
- Action Potentials physiology, Animals, Male, Neurons physiology, Patch-Clamp Techniques, Rats, Rats, Sprague-Dawley, Receptors, Neurokinin-1 metabolism, Solitary Nucleus physiology, Action Potentials drug effects, Adaptation, Physiological physiology, Hypoxia physiopathology, Neurons drug effects, Solitary Nucleus drug effects, Substance P pharmacology
- Abstract
NK1 receptors, which bind substance P, are present in the majority of brainstem regions that contain CO2/H(+)-sensitive neurons that play a role in central chemosensitivity. However, the effect of substance P on the chemosensitive response of neurons from these regions has not been studied. Hypoxia increases substance P release from peripheral afferents that terminate in the caudal nucleus tractus solitarius (NTS). Here we studied the effect of substance P on the chemosensitive responses of solitary complex (SC: NTS and dorsal motor nucleus) neurons from control and chronic hypoxia-adapted (CHx) adult rats. We simultaneously measured intracellular pH and electrical responses to hypercapnic acidosis in SC neurons from control and CHx adult rats using the blind whole cell patch clamp technique and fluorescence imaging microscopy. Substance P significantly increased the basal firing rate in SC neurons from control and CHx rats, although the increase was smaller in CHx rats. However, substance P did not affect the chemosensitive response of SC neurons from either group of rats. In conclusion, we found that substance P plays a role in modulating the basal firing rate of SC neurons but the magnitude of the effect is smaller for SC neurons from CHx adult rats, implying that NK1 receptors may be down regulated in CHx adult rats. Substance P does not appear to play a role in modulating the firing rate response to hypercapnic acidosis of SC neurons from either control or CHx adult rats.
- Published
- 2014
- Full Text
- View/download PDF
50. Signalling mechanisms of long term facilitation of breathing with intermittent hypoxia.
- Author
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Pamenter ME and Powell FL
- Abstract
Intermittent hypoxia causes long-term facilitation (LTF) of respiratory motor nerve activity and ventilation, which manifests as a persistent increase over the normoxic baseline for an hour or more after the acute hypoxic ventilatory response. LTF is likely involved in sleep apnea, but its exact role is uncertain. Previously, LTF was defined as a serotonergic mechanism, but new evidence shows that multiple signaling pathways can elicit LTF. This raises new questions about the interactions between signaling pathways in different time domains of the hypoxic ventilatory response, which can no longer be defined simply in terms of neurochemical mechanisms.
- Published
- 2013
- Full Text
- View/download PDF
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