30 results on '"Jandu S"'
Search Results
2. (1342) - Donor-Derived Cell-Free DNA in Pediatric Heart Transplant Patients
- Author
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Jandu, S., Long, D., Mahle, W., Ravichandran, V., and Mao, C.
- Published
- 2024
- Full Text
- View/download PDF
3. An In Situ Activity Assay for Lysyl Oxidases
- Author
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Wang, H., Poe, A., Pak, L., Jandu, S., Nandakumar, K., Steppan, J., Löser, R., Santhanam, L., Wang, H., Poe, A., Pak, L., Jandu, S., Nandakumar, K., Steppan, J., Löser, R., and Santhanam, L.
- Abstract
The lysyl oxidase family of enzymes (LOXs) catalyze oxidative deamination of lysine side chains on collagen and elastin to initialize cross-linking that is essential for the formation of the extracellular matrix (ECM). Elevated expression of LOXs is highly associated with diverse disease processes. To date, the inability to detect total LOX catalytic function in situ has limited the ability to fully elucidate the role of LOXs in pathobiological mechanisms. Using LOXL2 as a representative member of the LOX family, we developed an in situ activity assay by utilizing the strong reaction between hydrazide and aldehyde to label the LOX-catalyzed allysine (-CHO) residues with biotin-hydrazide. The biotinylated ECM proteins are then labeled via biotin-streptavidin interaction and detected by fluorescence microscopy. This assay detects the total LOX activity in situ for both overexpressed and endogenous LOXs in cells and tissue samples and can be used for studies of LOXs as therapeutic targets.
- Published
- 2021
4. (1342) - Donor-Derived Cell-Free DNA in Pediatric Heart Transplant Patients.
- Author
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Butto, A., Jandu, S., Long, D., Mahle, W., Ravichandran, V., and Mao, C.
- Subjects
- *
HEART transplant recipients , *CELL-free DNA , *CIRCULATING tumor DNA - Published
- 2024
- Full Text
- View/download PDF
5. Health promotion and participatory action research with South Asian women. (Health Policy and Systems)
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Choudhry, U.K., Jandu, S., Mahal, J., Singh, R., Sohi-Pabla, H., and Mutta, B.
- Subjects
Minority women -- Health aspects ,Health promotion -- Social aspects ,Immigrants -- Health aspects ,Indians in the United States -- Health aspects ,Health - Published
- 2002
6. Sacubitril-valsartan vs ACE/ARB in pediatric heart failure: A retrospective cohort study.
- Author
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Hale ZE, Prichett L, Jandu S, and Ravekes W
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- Humans, Retrospective Studies, Male, Female, Child, Child, Preschool, Adolescent, Infant, Treatment Outcome, Heart Transplantation, Propensity Score, Aminobutyrates therapeutic use, Biphenyl Compounds therapeutic use, Drug Combinations, Heart Failure drug therapy, Heart Failure mortality, Valsartan therapeutic use, Angiotensin Receptor Antagonists therapeutic use, Tetrazoles therapeutic use, Angiotensin-Converting Enzyme Inhibitors therapeutic use
- Abstract
Background: The first angiotensin receptor/neprilysin inhibitor on the market, sacubitril-valsartan, has shown marked improvements in death and hospitalization for heart failure among adults, and is now approved for use in pediatric heart failure. While the ongoing PANORAMA-HF trial is evaluating the effectiveness of sacubitril-valsartan for pediatric patients with a failing systemic left ventricle, the enrollment criteria do not include the majority of pediatric heart failure patients. Additional studies are needed., Methods: Using the TriNetX database, we performed a propensity score matched, retrospective cohort study to assess the incidence of a composite of all-cause mortality or heart transplant within 1 year. The 519 patients who received sacubitril-valsartan were compared to 519 matched controls who received an angiotensin converting enzyme inhibitor (ACE) or angiotensin II receptor blocker (ARB)., Results: There was no significant difference in the incidence of the composite outcome with sacubitril-valsartan over an ACE/ARB (13.3% vs 13.2%, p = 0.95), or among the components of mortality (5.0% vs 5.8%, p = 0.58) or heart transplantation (8.7% vs 7.5%, p = 0.50). Patients who were receiving full goal-directed medical therapy (14.4% vs 16.0%, p = 0.55) also showed no difference in the composite outcome. We observed a significantly increased incidence of hypotension (10% vs 5.2%, p = 0.006) and a trend toward reduced number of hospitalizations per year (mean (SD) 1.3 (4.4) vs 2.0 (9.1), p = 0.09)., Conclusions: Sacubitril-valsartan is not associated with a decrease in the composite of all-cause mortality or heart transplantation within 1 year. Future studies should evaluate the possible reduction in hospitalizations and optimal dosing to minimize hypotension., Competing Interests: Disclosure statement Z.E.H., L.P., S.J., and W.R. report no conflicts of interest for this work. This work was not financially supported. This work has been accepted for abstract presentation at the American Academy of Pediatrics and the World Congress of Pediatric Cardiology and Cardiac Surgery, (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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7. Optimization of resting tension for wire myography in male rat pulmonary arteries.
- Author
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Choi R, Narayanan R, Jandu S, Savage W, Kang S, Wodu B, Nandakumar K, Santhanam L, and Steppan J
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- Rats, Male, Animals, Phenylephrine, Myography methods, Vasodilation, Pulmonary Artery, Hypertension, Pulmonary
- Abstract
Wire myography to test vasomotor functions of blood vessels ex-vivo are well-established for the systemic circulation, however, there is no consensus on protocols for pulmonary arteries. We created a standardized wire myography protocol for healthy rat PAs and validated this in a pulmonary hypertension (PH) model. Vessels stretched to higher initial tensions (5.0, 7.5 and 10.0 mN) exhibited a uniform response to phenylephrine, a larger dynamic range, and lower EC50 values. The endothelium-mediated relaxation showed that moderate tensions (7.5 and 10.0 mN) produced robust responses with higher maximum relaxation and lower EC50 values. For endothelium independent responses, the higher initial tension groups had lower and more consistent EC50 values than the lower initial tension groups. Pulmonary arteries from rats with PH were more responsive to vasoactive drugs when subjected to a higher initial tension. Notably, vessels in the PH group subjected to 15.0 mN exhibited high dynamic ranges in contractile and relaxation responses without tearing. Lastly, we observed attenuated cholinergic responses in these vessels-consistent with endothelial dysfunction in PH. Therefore, a moderate initial tension of 7.5-10.0 mN is optimal for healthy rat pulmonary arteries and a higher initial tension of 15.0 mN is optimal for pulmonary arteries from animals with PH., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)
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- 2024
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8. Skeleton-secreted PDGF-BB mediates arterial stiffening.
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Santhanam L, Liu G, Jandu S, Su W, Wodu BP, Savage W, Poe A, Liu X, Alexander LM, Cao X, and Wan M
- Subjects
- Aging, Animals, Becaplermin blood, Bone Resorption etiology, Diet, High-Fat, Humans, Male, Mice, Mice, Inbred C57BL, Muscle, Smooth, Vascular cytology, Myocytes, Smooth Muscle physiology, Rats, Rats, Sprague-Dawley, Becaplermin physiology, Osteoclasts physiology, Vascular Stiffness physiology
- Abstract
Evidence links osteoporosis and cardiovascular disease but the cellular and molecular mechanisms are unclear. Here we identify skeleton-secreted platelet-derived growth factor-BB (PDGF-BB) as a key mediator of arterial stiffening in response to aging and metabolic stress. Aged mice and those fed high-fat diet (HFD), relative to young mice and those fed normal chow food diet, respectively, had higher serum PDGF-BB and developed bone loss and arterial stiffening. Bone/bone marrow preosteoclasts in aged mice and HFD mice secrete an excessive amount of PDGF-BB, contributing to the elevated PDGF-BB in blood circulation. Conditioned medium prepared from preosteoclasts stimulated proliferation and migration of the vascular smooth muscle cells. Conditional transgenic mice, in which PDGF-BB is overexpressed in preosteoclasts, had 3-fold higher serum PDGF-BB concentration and developed simultaneous bone loss and arterial stiffening spontaneously at a young age. Conversely, in conditional knockout mice, in which PDGF-BB is deleted selectively in preosteoclasts, HFD did not affect serum PDGF-BB concentration; as a result, HFD-induced bone loss and arterial stiffening were attenuated. These studies confirm that preosteoclasts are a main source of excessive PDGF-BB in blood circulation during aging and metabolic stress and establish the role of skeleton-derived PDGF-BB as an important mediator of vascular stiffening.
- Published
- 2021
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9. Author Correction: An in situ activity assay for lysyl oxidases.
- Author
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Wang H, Poe A, Pak L, Nandakumar K, Jandu S, Steppan J, Löser R, and Santhanam L
- Published
- 2021
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10. Probing tissue transglutaminase mediated vascular smooth muscle cell aging using a novel transamidation-deficient Tgm2-C277S mouse model.
- Author
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Wang H, Chen J, Jandu S, Melucci S, Savage W, Nandakumar K, Kang SK, Barreto-Ortiz S, Poe A, Rastogi S, Bauer M, Steppan J, and Santhanam L
- Abstract
Tissue transglutaminase (TG2), a multifunctional protein of the transglutaminase family, has putative transamidation-independent functions in aging-associated vascular stiffening and dysfunction. Developing preclinical models will be critical to fully understand the physiologic relevance of TG2's transamidation-independent activity and to identify the specific function of TG2 for therapeutic targeting. Therefore, in this study, we harnessed CRISPR-Cas9 gene editing technology to introduce a mutation at cysteine 277 in the active site of the mouse Tgm2 gene. Heterozygous and homozygous Tgm2-C277S mice were phenotypically normal and were born at the expected Mendelian frequency. TG2 protein was ubiquitously expressed in the Tgm2-C277S mice at levels similar to those of wild-type (WT) mice. In the Tgm2-C277S mice, TG2 transglutaminase function was successfully obliterated, but the transamidation-independent functions ascribed to GTP, fibronectin, and integrin binding were preserved. In vitro, a remodeling stimulus led to the significant loss of vascular compliance in WT mice, but not in the Tgm2-C277S or TG2
-/- mice. Vascular stiffness increased with age in WT mice, as measured by pulse-wave velocity and tensile testing. Tgm2-C277S mice were protected from age-associated vascular stiffening, and TG2 knockout yielded further protection. Together, these studies show that TG2 contributes significantly to overall vascular modulus and vasoreactivity independent of its transamidation function, but that transamidation activity is a significant cause of vascular matrix stiffening during aging. Finally, the Tgm2-C277S mice can be used for in vivo studies to explore the transamidation-independent roles of TG2 in physiology and pathophysiology., (© 2021. The Author(s).)- Published
- 2021
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11. An in situ activity assay for lysyl oxidases.
- Author
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Wang H, Poe A, Pak L, Nandakumar K, Jandu S, Steppan J, Löser R, and Santhanam L
- Subjects
- Amino Acid Oxidoreductases genetics, Amino Acid Oxidoreductases metabolism, Animals, Aorta enzymology, Biocatalysis, Blotting, Western, Cell Line, Fluorometry methods, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Protein-Lysine 6-Oxidase genetics, Rats, Mice, Enzyme Assays methods, Protein-Lysine 6-Oxidase metabolism
- Abstract
The lysyl oxidase family of enzymes (LOXs) catalyze oxidative deamination of lysine side chains on collagen and elastin to initialize cross-linking that is essential for the formation of the extracellular matrix (ECM). Elevated expression of LOXs is highly associated with diverse disease processes. To date, the inability to detect total LOX catalytic function in situ has limited the ability to fully elucidate the role of LOXs in pathobiological mechanisms. Using LOXL2 as a representative member of the LOX family, we developed an in situ activity assay by utilizing the strong reaction between hydrazide and aldehyde to label the LOX-catalyzed allysine (-CHO) residues with biotin-hydrazide. The biotinylated ECM proteins are then labeled via biotin-streptavidin interaction and detected by fluorescence microscopy. This assay detects the total LOX activity in situ for both overexpressed and endogenous LOXs in cells and tissue samples and can be used for studies of LOXs as therapeutic targets.
- Published
- 2021
- Full Text
- View/download PDF
12. Histamine Ingestion by Anopheles stephensi Alters Important Vector Transmission Behaviors and Infection Success with Diverse Plasmodium Species.
- Author
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Rodriguez AM, Hambly MG, Jandu S, Simão-Gurge R, Lowder C, Lewis EE, Riffell JA, and Luckhart S
- Subjects
- Animals, Anopheles parasitology, Disease Models, Animal, Female, Host-Parasite Interactions, Malaria parasitology, Malaria pathology, Mice, Mosquito Vectors parasitology, Anopheles drug effects, Histamine administration & dosage, Malaria transmission, Mosquito Vectors drug effects, Plasmodium falciparum physiology, Salivary Glands parasitology
- Abstract
An estimated 229 million people worldwide were impacted by malaria in 2019. The vectors of malaria parasites ( Plasmodium spp.) are Anopheles mosquitoes, making their behavior, infection success, and ultimately transmission of great importance. Individuals with severe malaria can exhibit significantly increased blood concentrations of histamine, an allergic mediator in humans and an important insect neuromodulator, potentially delivered to mosquitoes during blood-feeding. To determine whether ingested histamine could alter Anopheles stephensi biology, we provisioned histamine at normal blood levels and at levels consistent with severe malaria and monitored blood-feeding behavior, flight activity, antennal and retinal responses to host stimuli and lifespan of adult female Anopheles stephensi . To determine the effects of ingested histamine on parasite infection success, we quantified midgut oocysts and salivary gland sporozoites in mosquitoes infected with Plasmodium yoelii and Plasmodium falciparum . Our data show that provisioning An. stephensi with histamine at levels consistent with severe malaria can enhance mosquito behaviors and parasite infection success in a manner that would be expected to amplify parasite transmission to and from human hosts. Such knowledge could be used to connect clinical interventions by reducing elevated histamine to mitigate human disease pathology with the delivery of novel lures for improved malaria control.
- Published
- 2021
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13. A new open-access platform for measuring and sharing mTBI data.
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Domel AG, Raymond SJ, Giordano C, Liu Y, Yousefsani SA, Fanton M, Cecchi NJ, Vovk O, Pirozzi I, Kight A, Avery B, Boumis A, Fetters T, Jandu S, Mehring WM, Monga S, Mouchawar N, Rangel I, Rice E, Roy P, Sami S, Singh H, Wu L, Kuo C, Zeineh M, Grant G, and Camarillo DB
- Subjects
- Humans, Mouth Protectors, Neural Networks, Computer, Reproducibility of Results, Support Vector Machine, Access to Information, Algorithms, Brain Injuries, Traumatic diagnosis, Information Dissemination
- Abstract
Despite numerous research efforts, the precise mechanisms of concussion have yet to be fully uncovered. Clinical studies on high-risk populations, such as contact sports athletes, have become more common and give insight on the link between impact severity and brain injury risk through the use of wearable sensors and neurological testing. However, as the number of institutions operating these studies grows, there is a growing need for a platform to share these data to facilitate our understanding of concussion mechanisms and aid in the development of suitable diagnostic tools. To that end, this paper puts forth two contributions: (1) a centralized, open-access platform for storing and sharing head impact data, in collaboration with the Federal Interagency Traumatic Brain Injury Research informatics system (FITBIR), and (2) a deep learning impact detection algorithm (MiGNet) to differentiate between true head impacts and false positives for the previously biomechanically validated instrumented mouthguard sensor (MiG2.0), all of which easily interfaces with FITBIR. We report 96% accuracy using MiGNet, based on a neural network model, improving on previous work based on Support Vector Machines achieving 91% accuracy, on an out of sample dataset of high school and collegiate football head impacts. The integrated MiG2.0 and FITBIR system serve as a collaborative research tool to be disseminated across multiple institutions towards creating a standardized dataset for furthering the knowledge of concussion biomechanics.
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- 2021
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14. Aging and chronic high-fat feeding negatively affect kidney size, function, and gene expression in CTRP1-deficient mice.
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Rodriguez S, Little HC, Daneshpajouhnejad P, Fenaroli P, Tan SY, Sarver DC, Delannoy M, Talbot CC Jr, Jandu S, Berkowitz DE, Pluznick JL, Rosenberg AZ, and Wong GW
- Subjects
- Adipokines genetics, Age Factors, Aging genetics, Aging pathology, Animals, Chemokine CCL17 blood, Female, Gene Expression Regulation, Genotype, Hypertrophy, Kidney ultrastructure, Kidney Diseases genetics, Kidney Diseases metabolism, Kidney Diseases pathology, Male, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Tissue Inhibitor of Metalloproteinase-1 blood, Mice, Adipokines deficiency, Aging metabolism, Diet, High-Fat adverse effects, Kidney metabolism, Kidney Diseases etiology, Obesity etiology
- Abstract
C1q/TNF-related protein 1 (CTRP1) is an endocrine factor with metabolic, cardiovascular, and renal functions. We previously showed that aged Ctrp1- knockout (KO) mice fed a control low-fat diet develop renal hypertrophy and dysfunction. Since aging and obesity adversely affect various organ systems, we hypothesized that aging, in combination with obesity induced by chronic high-fat feeding, would further exacerbate renal dysfunction in CTRP1-deficient animals. To test this, we fed wild-type and Ctrp1- KO mice a high-fat diet for 8 mo or longer. Contrary to our expectation, no differences were observed in blood pressure, heart function, or vascular stiffness between genotypes. Loss of CTRP1, however, resulted in an approximately twofold renal enlargement (relative to body weight), ∼60% increase in urinary total protein content, and elevated pH, and changes in renal gene expression affecting metabolism, signaling, transcription, cell adhesion, solute and metabolite transport, and inflammation. Assessment of glomerular integrity, the extent of podocyte foot process effacement, as well as renal response to water restriction and salt loading did not reveal significant differences between genotypes. Interestingly, blood platelet, white blood cell, neutrophil, lymphocyte, and eosinophil counts were significantly elevated, whereas mean corpuscular volume and hemoglobin were reduced in Ctrp1 -KO mice. Cytokine profiling revealed increased circulating levels of CCL17 and TIMP-1 in KO mice. Compared with our previous study, current data suggest that chronic high-fat feeding affects renal phenotypes differently than similarly aged mice fed a control low-fat diet, highlighting a diet-dependent contribution of CTRP1 deficiency to age-related changes in renal structure and function.
- Published
- 2021
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15. Commonly used mouse strains have distinct vascular properties.
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Steppan J, Jandu S, Wang H, Kang S, Savage W, Narayanan R, Nandakumar K, and Santhanam L
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- Animals, Aorta anatomy & histology, Female, In Vitro Techniques, Male, Mice, Inbred C57BL anatomy & histology, Pulse Wave Analysis, Species Specificity, Aorta physiology, Mice, Inbred C57BL physiology, Vascular Stiffness
- Abstract
Mice are the most common animal model to investigate human disease and explore physiology. Mice are practical, cost efficient, and easily used for genetic manipulations. Although variability in cardiac structure and function among mouse strains is well noted, the effect of mouse strain on vascular stiffness indices is not known. Here, we compared mouse strain-dependent differences in key vascular stiffness indices among frequently used inbred mouse strains-C57Bl/6J, 129S, and Bl6/129S. In young healthy animals, baseline blood pressure and heart rate were identical in all strains, and independent of gender. However, both active in vivo and passive ex vivo vascular stiffness indices exhibited distinct differences. Specifically, both male and female 129S animals demonstrated the highest tensile stiffness, were least responsive to acetylcholine-induced vasorelaxation, and showed the lowest pulse wave velocity (PWV), an index of in vivo stiffness. C57Bl/6J mice demonstrated the highest PWV, lowest tensile stiffness, and the highest response to acetylcholine-induced vasorelaxation. Interestingly, within each strain, female mice had more compliant aortas. C57Bl/6J mice had thinner vessel walls with fewer layers, whereas 129S mice had the thickest walls with the most layers. Values in the Bl6/129S mixed background mice fell between C57Bl/6J and 129S mice. In conclusion, we show that underlying vascular properties of different inbred wild-type mouse strains are distinct, despite superficial similarities in blood pressure. For each genetic modification, care should be taken to identify proper controls, and conclusions might need to be verified in more than one strain to minimize the risk of false positive studies.
- Published
- 2020
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16. Restoring Blood Pressure in Hypertensive Mice Fails to Fully Reverse Vascular Stiffness.
- Author
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Steppan J, Jandu S, Savage W, Wang H, Kang S, Narayanan R, Nyhan D, and Santhanam L
- Abstract
Background: Hypertension is a well-established driver of vascular remodeling and stiffening. The goal of this study was to evaluate whether restoring normal blood pressure (BP) fully restores vascular stiffness toward that of normotensive controls., Methods: C57Bl6/J male mice received angiotensin II (angII; 1 μg/kg/min) via infusion pump for 8 weeks (hypertension group: HH), angII for 4 weeks (hypertension group: H4), angII for 4 weeks followed by 4 weeks of recovery (reversal group: HN), or sham treatment (normotensive group: NN). BP, heart rate, and pulse wave velocity (PWV) were measured longitudinally. At the end of the study period, aortas were harvested for testing of vasoreactivity, passive mechanical properties, and vessel structure., Results: The HH group exhibited a sustained increase in BP and PWV over the 8-week period ( p < 0.01). In the HN group, BP and PWV increased during the 4-week angII infusion, and, though BP was restored during the 4-week recovery, PWV exhibited only partial restoration ( p < 0.05). Heart rate was similar in all cohorts. Compared to NN controls, both HH and HN groups had significantly increased wall thickness ( p < 0.05 HH vs. NN, p < 0.01 HN vs. NN), mucosal extracellular matrix accumulation ( p < 0.0001 HH vs. NN, p < 0.05 HN vs. NN), and intralamellar distance ( p < 0.001 HH vs. NN, p < 0.01 HN vs. NN). Both intact and decellularized vessels were noted to have significantly higher passive stiffness in the HH and H4 cohorts than in NN controls ( p < 0.0001). However, in the HN cohort, intact vessels were only modestly stiffer than those of NN controls, and decellularized HN vessels were identical to those from the NN controls. Compared to NN controls, the HH and HN cohorts exhibited significantly diminished phenylephrine-induced contraction ( p < 0.0001) and endothelium-dependent vasodilation ( p < 0.05)., Conclusion: Hypertension causes a significant increase in in vivo aortic stiffness that is only partially reversible after BP normalization. Although hypertension does lead to matrix stiffening, restoration of BP restores matrix mechanics to levels similar to those of normotensive controls. Nevertheless, endothelial and vascular smooth muscle cell dysfunction persist after restoration of normotension. This dysfunction is, in part, responsible for augmented PWV after restoration of BP., (Copyright © 2020 Steppan, Jandu, Savage, Wang, Kang, Narayanan, Nyhan and Santhanam.)
- Published
- 2020
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17. Electrocardiographic changes in patients undergoing targeted temperature management.
- Author
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Jandu S, Sefa N, Sawyer KN, and Swor R
- Abstract
Objectives: Targeted temperature management is the recommended therapy for comatose patients after an out-of-hospital cardiac arrest resuscitation due to the reduction in neurological damage and improved outcomes. However, there may result in electrocardiographic instability depending on the degree of targeted temperature management, including minor or life-threatening dysrhythmias or conduction delays. This project aims to describe the frequency of ECG interval changes and clinically relevant dysrhythmias in targeted temperature management patients., Methods: This is a retrospective observational study from January 2009 to December 2015. Patients who qualified for the study had a non-traumatic cardiac arrest with a return of spontaneous circulation, received targeted temperature management at 33.5°C for 24 hours followed by 16 hours of rewarming. ECG interval changes and dysrhythmias were recorded immediately after return of spontaneous circulation, and at 24 and 48 hours post return of spontaneous circulation., Results: A total of 322 patients (age 61.0 ± 16.9 years) had targeted temperature management initiated during the study period, of which 169 had complete data and 13 died prior to completing 24 hours of hypothermia. There were statistically significant changes during targeted temperature management in heart rate (96.7 ± 26.0/min before targeted temperature management; 69.5 ± 19.1/min during, P < 0.001), QRS duration (115.1 ± 32.6 ms before targeted temperature management; 107.8 ± 27.9 ms during targeted temperature management, P < 0.001), and QTc (486.3 ± 52.8 ms before targeted temperature management; 526.9 ± 61.7 ms during targeted temperature management, P < 0.001). There were cardiac dysrhythmias that received treatment during cooling and rewarming., Conclusion: During the period of targeted temperature management and rewarming, we observed few self-limiting ECG interval changes and no clinically significant dysrhythmias in this population during the period of targeted temperature management., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of the American College of Emergency Physicians.)
- Published
- 2020
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18. Late-onset renal hypertrophy and dysfunction in mice lacking CTRP1.
- Author
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Rodriguez S, Little HC, Daneshpajouhnejad P, Shepard BD, Tan SY, Wolfe A, Cheema MU, Jandu S, Woodward OM, Talbot CC Jr, Berkowitz DE, Rosenberg AZ, Pluznick JL, and Wong GW
- Subjects
- Adipokines metabolism, Animals, Blood Pressure physiology, Hypertension physiopathology, Hypertrophy physiopathology, Inflammation metabolism, Inflammation physiopathology, Mice, Knockout, Signal Transduction physiology, Adipokines deficiency, Hypertension metabolism, Hypertrophy metabolism, Kidney metabolism
- Abstract
Local and systemic factors that influence renal structure and function in aging are not well understood. The secretory protein C1q/TNF-related protein 1 (CTRP1) regulates systemic metabolism and cardiovascular function. We provide evidence here that CTRP1 also modulates renal physiology in an age- and sex-dependent manner. In mice lacking CTRP1, we observed significantly increased kidney weight and glomerular hypertrophy in aged male but not female or young mice. Although glomerular filtration rate, plasma renin and aldosterone levels, and renal response to water restriction did not differ between genotypes, CTRP1-deficient male mice had elevated blood pressure. Echocardiogram and pulse wave velocity measurements indicated normal heart function and vascular stiffness in CTRP1-deficient animals, and increased blood pressure was not due to greater salt retention. Paradoxically, CTRP1-deficient mice had elevated urinary sodium and potassium excretion, partially resulting from reduced expression of genes involved in renal sodium and potassium reabsorption. Despite renal hypertrophy, markers of inflammation, fibrosis, and oxidative stress were reduced in CTRP1-deficient mice. RNA sequencing revealed alterations and enrichments of genes in metabolic processes in CTRP1-deficient animals. These results highlight novel contributions of CTRP1 to aging-associated changes in renal physiology., (© 2019 Federation of American Societies for Experimental Biology.)
- Published
- 2020
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19. Lysyl oxidase-like 2 depletion is protective in age-associated vascular stiffening.
- Author
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Steppan J, Wang H, Bergman Y, Rauer MJ, Tan S, Jandu S, Nandakumar K, Barreto-Ortiz S, Cole RN, Boronina TN, Zhu W, Halushka MK, An SS, Berkowitz DE, and Santhanam L
- Subjects
- Age Factors, Amino Acid Oxidoreductases genetics, Animals, Aorta, Thoracic enzymology, Aorta, Thoracic physiopathology, Aortic Diseases genetics, Aortic Diseases physiopathology, Cells, Cultured, Coculture Techniques, Endothelial Cells metabolism, Extracellular Matrix metabolism, Female, Humans, Male, Mice, Knockout, Muscle, Smooth, Vascular physiopathology, Nitric Oxide metabolism, Paracrine Communication, Signal Transduction, Vasoconstriction, Amino Acid Oxidoreductases deficiency, Aortic Diseases enzymology, Muscle, Smooth, Vascular enzymology, Myocytes, Smooth Muscle enzymology, Vascular Remodeling, Vascular Stiffness
- Abstract
Vascular stiffening and its sequelae are major causes of morbidity and mortality in the elderly. The increasingly accepted concept of "smooth muscle cell (SMC) stiffness syndrome" along with matrix deposition has emerged in vascular biology to account for the mechanical phenotype of arterial aging, but the molecular targets remain elusive. In this study, using an unbiased proteomic analysis, we identified lysyl oxidase-like 2 (LOXL2) as a critical SMC mediator for age-associated vascular stiffening. We tested the hypothesis that loss of LOXL2 function is protective in aging-associated vascular stiffening. We determined that exogenous and endogenous nitric oxide markedly decreased LOXL2 abundance and activity in the extracellular matrix of isolated SMCs and LOXL2 endothelial cells suppress LOXL2 abundance in the aorta. In a longitudinal study, LOXL2
+/- mice were protected from age-associated increase in pulse-wave velocity, an index of vascular stiffening, as occurred in littermate wild-type mice. Using isolated aortic segments, we found that LOXL2 mediates vascular stiffening in aging by promoting SMC stiffness, augmented SMC contractility, and vascular matrix deposition. Together, these studies establish LOXL2 as a nodal point for a new therapeutic approach to treat age-associated vascular stiffening. NEW & NOTEWORTHY Increased central vascular stiffness augments risk of major adverse cardiovascular events. Despite significant advances in understanding the genetic and molecular underpinnings of vascular stiffening, targeted therapy has remained elusive. Here, we show that lysyl oxidase-like 2 (LOXL2) drives vascular stiffening during aging by promoting matrix remodeling and vascular smooth muscle cell stiffening. Reduced LOXL2 expression protects mice from age-associated vascular stiffening and delays the onset of isolated systolic hypertension, a major consequence of stiffening.- Published
- 2019
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20. Alterations in endothelin type B receptor contribute to microvascular dysfunction in women who have had preeclampsia.
- Author
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Stanhewicz AE, Jandu S, Santhanam L, and Alexander LM
- Subjects
- Acetylcholine pharmacology, Adult, Biopsy, Endothelin-1 pharmacology, Endothelium, Vascular drug effects, Endothelium, Vascular pathology, Endothelium, Vascular physiopathology, Female, Galvanic Skin Response, Humans, Microdialysis, Nitric Oxide pharmacology, Norepinephrine pharmacology, Pregnancy, Receptor, Endothelin A, Signal Transduction drug effects, Skin pathology, Vasoconstriction drug effects, Vasodilation drug effects, Young Adult, Microvessels metabolism, Microvessels physiopathology, Pre-Eclampsia metabolism, Pre-Eclampsia physiopathology, Receptor, Endothelin B metabolism
- Abstract
Microvascular dysfunction originating during a preeclamptic pregnancy persists postpartum and probably contributes to increased CVD risk in these women. One putative mechanism contributing to this dysfunction is increased vasoconstrictor sensitivity to endothelin-1 (ET-1), mediated by alterations in ET-1 receptor type-B (ET
B R). We evaluated ET-1 sensitivity, ETA R, and ETB R contributions to ET-1-mediated constriction, and the mechanistic role of ETB R in endothelium-dependent dilation in vivo in the microvasculature of postpartum women who had preeclampsia (PrEC, n =12) and control women who had a healthy pregnancy (HC, n =12). We hypothesized that (1) PrEC would have a greater vasoconstrictor response to ET-1, and (2) reduced ETB R-mediated dilation. We further hypothesized that ETB R-blockade would attenuate endothelium-dependent vasodilation in HC, but not PrEC. Microvascular reactivity was assessed by measurement of cutaneous vascular conductance responses to graded infusion of ET-1 (10-20 -10-8 mol/l), ET-1 + 500 nmol/l BQ-123 (ETA R-blockade), and ET-1 + 300 nmol/l BQ-788 (ETB R-blockade), and during graded infusion of acetylcholine (ACh, 10-7 -102 mmol/l) and a standardized local heating protocol with and without ETB R-inhibition. PrEC had an increased vasoconstriction response to ET-1 ( P =0.02). PrEC demonstrated reduced dilation responses to selective ETB R stimulation with ET-1 ( P =0.01). ETB R-inhibition augmented ET-1-mediated constriction in HC ( P =0.01) but attenuated ET-1-mediated constriction in PrEC ( P =0.003). ETB R-inhibition attenuated endothelium-dependent vasodilation responses to 100mmol/l ACh ( P =0.04) and local heat ( P =0.003) in HC but increased vasodilation (ACh: P =0.01; local heat: P =0.03) in PrEC. Women who have had preeclampsia demonstrate augmented vasoconstrictor sensitivity to ET-1, mediated by altered ETB R signaling. Furthermore, altered ETB R function contributes to diminished endothelium-dependent dilation in previously preeclamptic women., (© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)- Published
- 2017
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21. Increased Angiotensin II Sensitivity Contributes to Microvascular Dysfunction in Women Who Have Had Preeclampsia.
- Author
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Stanhewicz AE, Jandu S, Santhanam L, and Alexander LM
- Subjects
- Adult, Angiotensin Receptor Antagonists pharmacology, Female, Humans, Losartan pharmacology, Pregnancy, Receptor, Angiotensin, Type 2 physiology, Angiotensin II metabolism, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, Endothelium, Vascular physiopathology, Hypertension etiology, Hypertension metabolism, Hypertension physiopathology, Microvessels drug effects, Microvessels metabolism, Microvessels physiopathology, Pre-Eclampsia metabolism, Pre-Eclampsia physiopathology, Vasodilation drug effects, Vasodilation physiology
- Abstract
Women who have had preeclampsia have increased cardiovascular disease risk; however, the mechanism(s) responsible for this association remain unclear. Microvascular damage sustained during a preeclamptic pregnancy may persist postpartum. The putative mechanisms mediating this dysfunction include a reduction in NO-dependent dilation and an increased sensitivity to angiotensin II. In this study, we evaluated endothelium-dependent dilation, angiotensin II sensitivity, and the therapeutic effect of angiotensin II receptor blockade (losartan) on endothelium-dependent dilation in vivo in the microvasculature of women with a history of preeclampsia (n=12) and control women who had a healthy pregnancy (n=12). We hypothesized that preeclampsia would have (1) reduced endothelium-dependent dilation, (2) reduced NO-mediated dilation, and (3) increased sensitivity to angiotensin II. We further hypothesized that localized losartan would increase endothelium-dependent vasodilation in preeclampsia. We assessed microvascular endothelium-dependent vasodilator function by measurement of cutaneous vascular conductance responses to graded infusion of acetylcholine (acetylcholine; 10
-7 -102 mmol/L) and a standardized local heating protocol in control sites and sites treated with 15 mmol/L L-NAME ( NG -nitro-l-arginine methyl ester; NO-synthase inhibitor) or 43 µmol/L losartan. Further, we assessed microvascular vasoconstrictor sensitivity to angiotensin II (10-20 -10-4 mol/L). Preeclampsia had significantly reduced endothelium-dependent dilation (-0.3±0.5 versus -1.0±0.4 logEC50 ; P <0.001) and NO-dependent dilation (16±3% versus 39±6%; P =0.006). Preeclampsia also had augmented vasoconstrictor sensitivity to angiotensin II (-10.2±1.3 versus -8.3±0.5; P =0.006). Angiotensin II type I receptor inhibition augmented endothelium-dependent vasodilation and NO-dependent dilation in preeclampsia but had no effect in healthy pregnancy. These data suggest that women who have had preeclampsia have persistent microvascular dysfunction postpartum, mediated, in part, by increased sensitivity to angiotensin II., (© 2017 American Heart Association, Inc.)- Published
- 2017
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22. Impaired Hydrogen Sulfide-Mediated Vasodilation Contributes to Microvascular Endothelial Dysfunction in Hypertensive Adults.
- Author
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Greaney JL, Kutz JL, Shank SW, Jandu S, Santhanam L, and Alexander LM
- Subjects
- Acetylcholine pharmacology, Blood Pressure drug effects, Endothelium, Vascular drug effects, Female, Humans, Laser-Doppler Flowmetry, Male, Microvessels drug effects, Middle Aged, Skin blood supply, Vasodilation drug effects, Blood Pressure physiology, Endothelium, Vascular physiopathology, Hydrogen Sulfide pharmacology, Hypertension physiopathology, Microvessels physiopathology, Vasodilation physiology
- Abstract
Reductions in hydrogen sulfide (H
2 S) production have been implicated in the pathogenesis of vascular dysfunction in animal models of hypertension; however, no studies have examined a functional role for H2 S in contributing to microvascular dysfunction in hypertensive (HTN) adults. We hypothesized that endogenous production of H2 S would be reduced, impaired endothelium-dependent vasodilation would be mediated by reductions in H2 S-dependent vasodilation, and vascular responsiveness to exogenous H2 S (sodium sulfide) would be attenuated in HTN compared to normotensive adults. Fifteen normotensive (51±2 years; blood pressure, 116±3/76±3 mm Hg) and 14 HTN adults (57±2 years; blood pressure 140±3/89±2 mm Hg) participated. H2 S biosynthetic enzyme expression (Western blot) and substrate-dependent H2 S production (amperometric probe) were measured in cutaneous tissue homogenates. Red cell flux (laser Doppler flowmetry) was measured during graded perfusions of acetylcholine (ACh; 10-6 -10-1 mol/L) and sodium sulfide (10-5 -101 mol/L) using intradermal microdialysis; the functional role of H2 S was determined using pharmacological inhibition with aminooxyacetic acid (0.5 mmol/L). H2 S biosynthetic enzyme expression and substrate-dependent H2 S production were reduced in HTN adults (all P <0.05). ACh-induced endothelium-dependent vasodilation was blunted in HTN adults ( P =0.012). Aminooxyacetic acid attenuated ACh-induced vasodilation in normotensive adults (ACh, 1.31±0.13 versus ACh+aminooxyacetic acid, 1.07±0.09 flux/mm Hg; P =0.025) but had no effect on vasodilation in HTN adults (ACh, 1.16±0.10 versus ACh+aminooxyacetic acid, 1.37±0.11 flux/mm Hg; P =0.47). Sodium sulfide-induced vasodilation was not different between groups. Collectively, these findings indicate that while the microvasculature maintains the ability to vasodilate in response to exogenous H2 S, reductions in endogenous synthesis and H2 S-dependent vasodilation contribute to endothelial dysfunction in human hypertension., (© 2017 American Heart Association, Inc.)- Published
- 2017
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23. Cystathionine γ-lyase protects vascular endothelium: a role for inhibition of histone deacetylase 6.
- Author
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Leucker TM, Nomura Y, Kim JH, Bhatta A, Wang V, Wecker A, Jandu S, Santhanam L, Berkowitz D, Romer L, and Pandey D
- Subjects
- Animals, Apolipoproteins E genetics, Cystathionine gamma-Lyase biosynthesis, Cystathionine gamma-Lyase genetics, Endothelial Cells drug effects, Endothelial Cells metabolism, Endothelium, Vascular drug effects, Histone Deacetylase 6, Humans, Hydrogen Sulfide metabolism, Hydrogen Sulfide pharmacology, Lipoproteins, LDL toxicity, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Contraction, RNA, Messenger biosynthesis, RNA, Messenger genetics, Vasodilation drug effects, Vasodilation genetics, Cystathionine gamma-Lyase metabolism, Endothelium, Vascular enzymology, Endothelium, Vascular physiology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases genetics
- Abstract
Endothelial cystathionine γ-lyase (CSEγ) contributes to cardiovascular homeostasis, mainly through production of H
2 S. However, the molecular mechanisms that control CSEγ gene expression in the endothelium during cardiovascular diseases are unclear. The aim of the current study is to determine the role of specific histone deacetylases (HDACs) in the regulation of endothelial CSEγ. Reduced CSEγ mRNA expression and protein abundance were observed in human aortic endothelial cells (HAEC) exposed to oxidized LDL (OxLDL) and in aortas from atherogenic apolipoprotein E knockout (ApoE-/- ) mice fed a high-fat diet compared with controls. Intact murine aortic rings exposed to OxLDL (50 μg/ml) for 24 h exhibited impaired endothelium-dependent vasorelaxation that was blocked by CSEγ overexpression or the H2 S donor NaHS. CSEγ expression was upregulated by pan-HDAC inhibitors and by class II-specific HDAC inhibitors, but not by other class-specific inhibitors. The HDAC6 selective inhibitor tubacin and HDAC6-specific siRNA increased CSEγ expression and blocked OxLDL-mediated reductions in endothelial CSEγ expression and CSEγ promoter activity, indicating that HDAC6 is a specific regulator of CSEγ expression. Consistent with this finding, HDAC6 mRNA, protein expression, and activity were upregulated in OxLDL-exposed HAEC, but not in human aortic smooth muscle cells. HDAC6 protein levels in aortas from high-fat diet-fed ApoE-/- mice were comparable to those in controls, whereas HDAC6 activity was robustly upregulated. Together, our findings indicate that HDAC6 is upregulated by atherogenic stimuli via posttranslational modifications and is a critical regulator of CSEγ expression in vascular endothelium. Inhibition of HDAC6 activity may improve endothelial function and prevent or reverse the development of atherosclerosis. NEW & NOTEWORTHY Oxidative injury to endothelial cells by oxidized LDL reduced cystathionine γ-lyase (CSEγ) expression and H2 S production, leading to endothelial dysfunction, which was prevented by histone deacetylase 6 (HDAC6) inhibition. Our data suggest HDAC6 as a novel therapeutic target to prevent the development of atherosclerosis., (Copyright © 2017 the American Physiological Society.)- Published
- 2017
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24. Tissue Transglutaminase Modulates Vascular Stiffness and Function Through Crosslinking-Dependent and Crosslinking-Independent Functions.
- Author
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Steppan J, Bergman Y, Viegas K, Armstrong D, Tan S, Wang H, Melucci S, Hori D, Park SY, Barreto SF, Isak A, Jandu S, Flavahan N, Butlin M, An SS, Avolio A, Berkowitz DE, Halushka MK, and Santhanam L
- Subjects
- Animals, Aorta, Thoracic pathology, Aorta, Thoracic physiopathology, Apoptosis, Blotting, Western, Cell Differentiation, Cell Movement, Cell Proliferation, Cells, Cultured, Coronary Vessels cytology, Coronary Vessels enzymology, Humans, Immunohistochemistry, Male, Mice, Models, Animal, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular enzymology, Myography, Protein Glutamine gamma Glutamyltransferase 2, Pulse Wave Analysis, Tissue Array Analysis, Aorta, Thoracic enzymology, Collagen metabolism, Coronary Vessels physiology, GTP-Binding Proteins biosynthesis, Muscle, Smooth, Vascular physiology, Transglutaminases biosynthesis, Vascular Stiffness physiology
- Abstract
Background: The structural elements of the vascular wall, namely, extracellular matrix and smooth muscle cells (SMCs), contribute to the overall stiffness of the vessel. In this study, we examined the crosslinking-dependent and crosslinking-independent roles of tissue transglutaminase (TG2) in vascular function and stiffness., Methods and Results: SMCs were isolated from the aortae of TG2-/- and wild-type (WT) mice. Cell adhesion was examined by using electrical cell-substrate impedance sensing and PicoGreen assay. Cell motility was examined using a Boyden chamber assay. Cell proliferation was examined by electrical cell-substrate impedance sensing and EdU incorporation assays. Cell micromechanics were studied using magnetic torsion cytometry and spontaneous nanobead tracer motions. Aortic mechanics were examined by tensile testing. Vasoreactivity was studied by wire myography. SMCs from TG2-/- mice had delayed adhesion, reduced motility, and accelerated de-adhesion and proliferation rates compared with those from WT. TG2-/- SMCs were stiffer and displayed fewer cytoskeletal remodeling events than WT. Collagen assembly was delayed in TG2-/- SMCs and recovered with adenoviral transduction of TG2. Aortic rings from TG2-/- mice were less stiff than those from WT; stiffness was partly recovered by incubation with guinea pig liver TG2 independent of crosslinking function. TG2-/- rings showed augmented response to phenylephrine-mediated vasoconstriction when compared with WT. In human coronary arteries, vascular media and plaque, high abundance of fibronectin expression, and colocalization with TG2 were observed., Conclusions: TG2 modulates vascular function/tone by altering SMC contractility independent of its crosslinking function and contributes to vascular stiffness by regulating SMC proliferation and matrix remodeling., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)
- Published
- 2017
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25. MPST but not CSE is the primary regulator of hydrogen sulfide production and function in the coronary artery.
- Author
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Kuo MM, Kim DH, Jandu S, Bergman Y, Tan S, Wang H, Pandey DR, Abraham TP, Shoukas AA, Berkowitz DE, and Santhanam L
- Subjects
- Animals, Cells, Cultured, Coronary Vessels drug effects, Cystathionine gamma-Lyase antagonists & inhibitors, Cystathionine gamma-Lyase deficiency, Cystathionine gamma-Lyase genetics, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Humans, Kinetics, Male, Mice, Knockout, Nitric Oxide metabolism, Rats, Sprague-Dawley, Signal Transduction drug effects, Vasodilation drug effects, Vasodilator Agents pharmacology, Coronary Vessels enzymology, Cystathionine gamma-Lyase metabolism, Hydrogen Sulfide metabolism, Sulfurtransferases metabolism
- Abstract
Hydrogen sulfide (H2S) has emerged as an important gasotransmitter in the vasculature. In this study, we tested the hypothesis that H2S contributes to coronary vasoregulation and evaluated the physiological relevance of two sources of H2S, namely, cystathionine-γ-lyase (CSE) and 3-mercaptypyruvate sulfertransferase (MPST). MPST was detected in human coronary artery endothelial cells as well as rat and mouse coronary artery; CSE was not detected in the coronary vasculature. Rat coronary artery homogenates produced H2S through the MPST pathway but not the CSE pathway in vitro. In vivo coronary vasorelaxation response was similar in CSE knockout mice, wild-type mice (WT), and WT mice treated with the CSE inhibitor propargylglycine, suggesting that CSE-produced H2S does not have a significant role in coronary vasoregulation in vivo. Ex vivo, the MPST substrate 3-mercaptopyruvate (3-MP) and H2S donor sodium hydrosulfide (NaHS) elicited similar coronary vasoreactivity responses. Pyruvate did not have any effects on vasoreactivity. The vasoactive effect of H2S appeared to be nitric oxide (NO) dependent: H2S induced coronary vasoconstriction in the presence of NO and vasorelaxation in its absence. Maximal endothelial-dependent relaxation was intact after 3-MP and NaHS induced an increase in preconstriction tone, suggesting that endothelial NO synthase activity was not significantly inhibited. In vitro, H2S reacted with NO, which may, in part explain the vasoconstrictive effects of 3-MP and NaHS. Taken together, these data show that MPST rather than CSE generates H2S in coronary artery, mediating its effects through direct modulation of NO. This has important implications for H2S-based therapy in healthy and diseased coronary arteries., (Copyright © 2016 the American Physiological Society.)
- Published
- 2016
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26. Exercise, vascular stiffness, and tissue transglutaminase.
- Author
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Steppan J, Sikka G, Jandu S, Barodka V, Halushka MK, Flavahan NA, Belkin AM, Nyhan D, Butlin M, Avolio A, Berkowitz DE, and Santhanam L
- Subjects
- Age Factors, Animals, Arterial Pressure, Cell Adhesion Molecules metabolism, Male, Microfilament Proteins metabolism, Nitric Oxide Synthase Type III metabolism, Phosphoproteins metabolism, Phosphorylation, Protein Glutamine gamma Glutamyltransferase 2, Pulse Wave Analysis, Rats, Rats, Inbred F344, Running, Signal Transduction, Tensile Strength, Aging metabolism, Aorta enzymology, Aorta physiopathology, GTP-Binding Proteins metabolism, Physical Exertion, Transglutaminases metabolism, Vascular Stiffness
- Abstract
Background: Vascular aging is closely associated with increased vascular stiffness. It has recently been demonstrated that decreased nitric oxide (NO)-induced S-nitrosylation of tissue transglutaminase (TG2) contributes to age-related vascular stiffness. In the current study, we tested the hypothesis that exercise restores NO signaling and attenuates vascular stiffness by decreasing TG2 activity and cross-linking in an aging rat model., Methods and Results: Rats were subjected to 12 weeks of moderate aerobic exercise. Aging was associated with diminished phosphorylated endothelial nitric oxide synthase and phosphorylated vasodilator-stimulated phosphoprotein abundance, suggesting reduced NO signaling. TG2 cross-linking activity was significantly increased in old animals, whereas TG2 abundance remained unchanged. These alterations were attenuated in the exercise cohort. Simultaneous measurement of blood pressure and pulse wave velocity (PWV) demonstrated increased aortic stiffness in old rats, compared to young, at all values of mean arterial pressure (MAP). The PWV-MAP correlation in the old sedentary and old exercise cohorts was similar. Tensile testing of the vessels showed increased stiffness of the aorta in the old phenotype with a modest restoration of mechanical properties toward the young phenotype with exercise., Conclusions: Increased vascular stiffness during aging is associated with decreased TG2 S-nitrosylation, increased TG2 cross-linking activity, and increased vascular stiffness likely the result of decreased NO bioavailability. In this study, a brief period of moderate aerobic exercise enhanced NO signaling, attenuated TG cross-linking activity, and reduced ex vivo tensile properties, but failed to reverse functional vascular stiffness in vivo, as measured by PWV.
- Published
- 2014
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27. Increased tissue transglutaminase activity contributes to central vascular stiffness in eNOS knockout mice.
- Author
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Jung SM, Jandu S, Steppan J, Belkin A, An SS, Pak A, Choi EY, Nyhan D, Butlin M, Viegas K, Avolio A, Berkowitz DE, and Santhanam L
- Subjects
- Animals, Enzyme Activation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide Synthase Type III genetics, Protein Glutamine gamma Glutamyltransferase 2, Stress, Mechanical, Tensile Strength physiology, Aorta physiology, Blood Pressure physiology, Endothelium, Vascular physiology, GTP-Binding Proteins biosynthesis, Nitric Oxide Synthase Type III metabolism, Transglutaminases biosynthesis, Vascular Stiffness physiology
- Abstract
Nitric oxide (NO) can modulate arterial stiffness by regulating both functional and structural changes in the arterial wall. Tissue transglutaminase (TG2) has been shown to contribute to increased central aortic stiffness by catalyzing the cross-linking of matrix proteins. NO S-nitrosylates and constrains TG2 to the cytosolic compartment and thereby holds its cross-linking function latent. In the present study, the role of endothelial NO synthase (eNOS)-derived NO in regulating TG2 function was studied using eNOS knockout mice. Matrix-associated TG2 and TG2 cross-linking function were higher, whereas TG2 S-nitrosylation was lower in the eNOS(-/-) compared with wild-type (WT) mice. Pulse-wave velocity (PWV) and blood pressure measured noninvasively were elevated in the eNOS(-/-) compared with WT mice. Intact aortas and decellularized aortic tissue scaffolds of eNOS(-/-) mice were significantly stiffer, as determined by tensile testing. The carotid arteries of the eNOS(-/-) mice were also stiffer, as determined by pressure-dimension analysis. Invasive methods to determine the PWV-mean arterial pressure relationship showed that PWV in eNOS(-/-) and WT diverge at higher mean arterial pressure. Thus eNOS-derived NO regulates TG2 localization and function and contributes to vascular stiffness.
- Published
- 2013
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- View/download PDF
28. A survey of South Asian attitudes to organ donation in the United Kingdom.
- Author
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Karim A, Jandu S, and Sharif A
- Subjects
- Adolescent, Adult, Aged, Cross-Sectional Studies, Female, Health Knowledge, Attitudes, Practice, Humans, Male, Middle Aged, Prognosis, Religion, Surveys and Questionnaires, United Kingdom, Young Adult, Asian People psychology, Attitude to Health, Organ Transplantation psychology, Tissue Donors psychology, Tissue and Organ Procurement organization & administration
- Abstract
Background: South Asians in the United Kingdom are overrepresented on the organ transplant waiting list but underrepresented as organ donors. In this study, we surveyed South Asian opinion with regards to organ donation., Methods: Voluntary completion of an anonymous survey was promoted amongst South Asians by both online and paper-based approaches. Logistic regression analysis was performed to assess independent predictors for organ donation approval., Results: Five hundred and fifty-six survey responses were analyzed in this study. 68.4% of respondents agreed with organ donation but only 13.3% were registered organ donors. Muslims were less likely than Hindus or Sikhs to agree with organ donation (59.3% vs. 92.2% vs. 88.7%, p < 0.001) or be registered donors (5.0% vs. 40.3% vs. 25.8%, p < 0.001), respectively. Religious guidance was important for Muslims, but parental approval of greater importance for Hindus. On logistic regression analysis, variables independently associated with organ donation approval were; young age, independent living from parents, non-Muslims, awareness of organ donation shortages, family member on dialysis/registered donor, and more liberal degrees of religious belief (all p < 0.05)., Conclusion: South Asians in the United Kingdom are a heterogeneous group of different faiths, cultures, and values. We believe targeted strategies are required to raise awareness of organ donation amongst South Asians., (© 2013 John Wiley & Sons A/S.)
- Published
- 2013
- Full Text
- View/download PDF
29. 13C NMR study of the effects of mutation on the tryptophan dynamics in chymotrypsin inhibitor 2: correlations with structure and stability.
- Author
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Matthews SJ, Jandu SK, and Leatherbarrow RJ
- Subjects
- Base Sequence, Carbon Isotopes, Magnetic Resonance Spectroscopy, Molecular Sequence Data, Oligodeoxyribonucleotides, Peptides, Plant Proteins genetics, Plant Proteins isolation & purification, Protein Folding, Mutation, Plant Proteins chemistry, Tryptophan chemistry
- Abstract
Recombinant chymotrypsin inhibitor 2 (CI-2) and the three mutants Ile39-->Val, Ile39-->Leu, and Arg67-->Ala were successfully enriched with [2-13C]tryptophan at position 24 within the hydrophobic core of the protein. Carbon-13 NMR relaxation measurements were then used to investigate the effect of these mutations on the dynamics of the tryptophan residue. In addition, the stability of wild-type and mutant CI-2s was measured by their susceptibility to unfolding by guanidine hydrochloride. The mutant proteins were all found to be less stable, giving delta delta GU values relative to wild-type of 1.17, 1.96, and 1.21 kcal mol-1, respectively. The indole moiety of the tryptophan residue was found to be more mobile in all the mutants studied than in wild-type CI-2. Order parameters of 0.69, 0.60, 0.56, and 0.44 were derived for wild-type, Ile39-->Val, Ile39-->Leu, and Arg67-->Ala CI-2, respectively. It is concluded that there is a correlation between the protein stability and the picosecond dynamics within the hydrophobic core and that mutations can influence the dynamic behavior of the residues that are relatively distant in the three-dimensional structure.
- Published
- 1993
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30. Role of arginine 67 in the stabilization of chymotrypsin inhibitor 2: examination of amide proton exchange rates and denaturation thermodynamics of an engineered protein.
- Author
-
Jandu SK, Ray S, Brooks L, and Leatherbarrow RJ
- Subjects
- Arginine, Base Sequence, Hordeum, Hydrogen Bonding, Kinetics, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Peptides, Plant Proteins genetics, Protein Conformation, Protein Denaturation, Protein Engineering, Thermodynamics, Plant Proteins metabolism, Serine Proteinase Inhibitors metabolism
- Abstract
We have examined the contribution to protein stability of an interaction involving a charged hydrogen bond from an arginyl side chain (Arg67) in the serine proteinase inhibitor chymotrypsin inhibitor 2 (CI-2), by replacing this side chain with an alanyl residue by protein engineering. Using nuclear magnetic resonance spectroscopy (NMR), we have examined the effect of this mutation on the hydrogen-deuterium exchange rates of several backbone amide protons in the native and engineered proteins at 50 degrees C. These exchange rates provide a localized probe at multiple discrete sites throughout the protein and from comparison of native and mutant exchange rates allow calculation of the difference in free energy of exchange (delta delta Gex) resulting from the mutation. The results show that for the majority of amides observed this mutation results in delta delta Gex of ca. 1.7 kcal mol-1 over the whole CI-2 molecule. However, for two relatively exposed amide protons the exchange rates are found to be far less perturbed, implying that local unfolding mechanisms predominate for these protons. Direct measurement of the stability of both proteins to denaturation by guanidinum hydrochloride shows that the interaction contributes 1.4 kcal mol-1 to the stability of the molecule. This value is comparable to those obtained from the NMR exchange measurements and indicates that the exchange processes reflect the differences in stability between the native and mutant proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1990
- Full Text
- View/download PDF
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