Search

Takehara N, Makita N, Kawabe J, Sato N, Kawamura Y, Kitabatake A, Kikuchi K (Asahikawa Medical College, Asahikawa; Hokkaido University Graduate School of Medicine, Sapporo, Japan; and Cardiovascular Research Institute, Newark, NY, USA). A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill (Case Report). J Intern Med 2004; 255: 137–142. Mutations in the cardiac Na+ channel gene SCN5A are responsible for multiple lethal ventricular arrhythmias including Brugada syndrome and congenital long QT syndrome. Here we report a case of Brugada syndrome with ST elevation in the right precordial and inferior leads accompanied by atrial standstill and spontaneous ventricular fibrillation. Atrial standstill and J wave elevation were provoked by procainamide. Genetic analysis revealed a missense mutation (R367H) in SCN5A. The resultant mutant Na+ channel was nonfunctional when expressed heterologously in Xenopus oocytes. Our study suggests that genetic defects in SCN5A may be associated with atrial standstill in combination with ventricular arrhythmias. [ABSTRACT FROM AUTHOR]

Here, next-generation RNA sequencing analysis was performed to develop 13 novel expressed sequence tag-simple sequence repeat markers to evaluate the genetic variation in the near-threatened halophyte, Limonium tetragonum (Thunb.) A. A. Bullock. In the four populations, the total number of alleles at each locus ranged from two to seven, with an average of 3.1 and average observed and expected heterozygosities ranged from 0.00 to 0.13 and 0.28 to 0.78, respectively. Three of thirteen loci had the same homo alleles within populations, however, different alleles among different populations. Compared to other halophytes, relatively low genetic diversity was observed in this species. Further studies are necessary to determine the population demography of L. tetragonum and clarify the cause of its low genetic diversity.

Ischemic preconditioning (IPC) describes a phenomenon wherein brief ischemia of the heart induces a potent cardioprotective mechanism against succeeding ischemic insult. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostanoid biosynthesis, is upregulated in the ischemic heart and contributes to IPC. Prostaglandin E 2 (PGE 2 ) protects the heart from ischemia-reperfusion (I/R) injury via its receptor subtype EP 4 . We sought to clarify the role of the PGE 2 /EP 4 system in the late phase of IPC. Mice were subjected to four IPC treatment cycles, consisting of 5 min of occlusion of the left anterior descending coronary artery (LAD). We found that COX-2 mRNA was significantly upregulated in wild-type hearts at 6 h after IPC treatment. Cardiac PGE 2 levels at 24 h after IPC treatment were significantly increased in both wild-type mice and mice lacking EP 4 (EP 4 -/- ). At 24 h after IPC treatment, I/R injury was induced by 30 min of LAD occlusion followed by 2 h of reperfusion and the cardiac infarct size was determined. The infarct size was significantly reduced by IPC treatment in wild-type mice; a reduction was not observed in EP 4 -/- mice. AE1-329, an EP 4 agonist, significantly reduced infarct size and significantly ameliorated deterioration of cardiac function in wild-type mice subjected to I/R without IPC treatment. Furthermore, AE1-329 significantly enhanced the I/R-induced activation of Akt, a pro-survival kinase. We demonstrated that the PGE 2 /EP 4 system in the heart plays a critical role in the late phase of IPC, partly by augmenting Akt-mediated signaling. These findings clarify the mechanism of IPC and may contribute to the development of therapeutic strategies for ischemic heart disease., (© 2022. The Author(s).)

Sarcopenia is a pathophysiological malfunction induced by skeletal muscle atrophy. Several studies reported an association between sarcopenia-induced cardiac cachexia and poor prognosis in heart disease. However, due to lack of an established animal models, the underlying mechanism of disturbed cardiac repair accompanied with sarcopenia remains poorly understood. Here, we developed a novel sarcopenia-induced cardiac repair disturbance mouse model induced by tail suspension (TS) after cardiac ischemia and reperfusion (I/R). Importantly, we identified a specific exosomal-microRNA marker, miR-16-5p, in the circulating exosomes of I/R-TS mice. Of note, sarcopenia after I/R disturbed cardiac repair and raised the level of circulating-exosomal-miR-16-5p secreting from both the atrophic limbs and heart of TS mice. Likewise, miR-16-5p mimic plasmid disturbed cardiac repair in I/R mice directly. Additionally, in neonatal rat ventricular myocytes (NRVMs) cultured in vitro under hypoxic conditions in the presence of a miR-16-5p mimic, we observed increased apoptosis through p53 and Caspase3 upregulation, and also clarified that autophagosomes were decreased in NRVMs via SESN1 transcript interference-mediated mTOR activation. In conclusion, we show the pro-apoptotic effect of sarcopenia-derived miR-16-5p, which may be behind the exacerbation of myocardial infarction. Therefore, miR-16-5p can be a novel therapeutic target in the context of cardiac repair disturbances in sarcopenia-cachexia., (© 2021. The Author(s).)

Adventitial abnormalities including enhanced vasa vasorum malformation are associated with development and vulnerability of atherosclerotic plaque. However, the mechanisms of vasa vasorum malformation and its role in vascular remodeling have not been fully clarified. We recently reported that ninjurin-1 (Ninj1) is a crucial adhesion molecule for pericytes to form matured neovessels. The purpose is to examine if Ninj1 regulates adventitial angiogenesis and affects the vascular remodeling of injured vessels using pericyte-specific Ninj1 deletion mouse model. Mouse femoral arteries were injured by insertion of coiled wire. Four weeks after vascular injury, fixed arteries were decolorized. Vascular remodeling, including intimal hyperplasia and adventitial microvessel formation were estimated in a three-dimensional view. Vascular fragility, including blood leakiness was estimated by extravasation of fluorescein isothiocyanate (FITC)-lectin or FITC-dextran from microvessels. Ninj1 expression was increased in pericytes in response to vascular injury. NG2-CreER/ Ninj1 loxp mice were treated with tamoxifen (Tam) to induce deletion of Ninj1 in pericyte ( Ninj1 KO). Tam-treated NG2-CreER or Tam-nontreated NG2-CreER/ Ninj1 loxp mice were used as controls. Intimal hyperplasia was significantly enhanced in Ninj1 KO compared with controls. Vascular leakiness was significantly enhanced in Ninj1 KO. In Ninj1 KO, the number of infiltrated macrophages in adventitia was increased, along with the expression of inflammatory cytokines. In conclusion, deletion of Ninj1 in pericytes induces the immature vasa vasorum formation of injured vasculature and exacerbates adventitial inflammation and intimal hyperplasia. Thus, Ninj1 contributes to the vasa vasorum maturation in response to vascular injury and to reduction of vascular remodeling. NEW & NOTEWORTHY Although abnormalities of adventitial vasa vasorum are associated with vascular remodeling such as atherosclerosis, the mechanisms of vasa vasorum malformation and its role in vascular remodeling have not been fully clarified. The present study provides a line of novel evidence that ninjurin-1 contributes to adventitial microvascular maturation during vascular injury and regulates vascular remodeling.

Skeletal muscle has a capacity for muscular regeneration mediated by satellite cells (SCs) and non-SCs. Although it is proposed that non-SCs are attractive therapeutic targets for dystrophies, the biological properties of these cells remain unclear. We have recently identified novel multipotent pericytes (PCs), capillary stem cells (CapSCs) derived from the microvasculature. In the present study, we determined if CapSCs contributed to myogenic regeneration using muscular dystrophy mouse model. CapSCs were isolated as EphA7 + NG2 + PCs from the subcutaneous adipose tissues of GFP-transgenic mice. Co-culture with C2C12 myoblast cells showed that CapSCs effectively enhanced myogenesis as compared to controls including EphA7 - PCs and adipose stromal cells (ASCs). CapSCs transplanted in cardiotoxin-injured gastrocnemius muscles were well differentiated into both muscle fibers and microvessels, as compared to controls. At three weeks after cell-transplantation into the limbs of the mdx/utrn -/- mouse, CapSCs increased the number of GFP + myofibers along with dystrophin expression and the area size of myofibers, and also enhanced the muscular mass and its performance, assessed by treadmill test as compared to controls. In conclusion, CapSCs have potent myogenic regeneration capacity and improved the pathological condition in a muscular dystrophy mouse. Thus, CapSCs are an attractive cellular source in regenerative therapy for muscular dystrophy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

The presence of pericytes (PCs) with multipotency and broad distribution along capillary suggests that microvasculature plays a role not only as a duct for blood fluid transport but also as a stem cell niche that contributes to tissue maintenance and regeneration. The lack of an appropriate marker for multipotent PCs still limits our understanding of their pathophysiological roles. We identified the novel marker EphA7 to detect multipotent PCs using microarray analysis of an immortalized PC library. PCs were isolated from microvessels of mouse subcutaneous adipose tissues, then EphA7 + PCs called capillary stem cells (CapSCs) were separated from EphA7 - control PCs (ctPCs) using fluorescence-activated cell sorting system. CapSCs had highly multipotency that enabled them to differentiate into mesenchymal and neuronal lineages compared with ctPCs. CapSCs also differentiated into endothelial cells and PCs to form capillary-like structures by themselves. Transplantation of CapSCs into ischemic tissues significantly improved blood flow recovery in hind limb ischemia mouse model due to vascular formation compared with that of ctPCs and adipose stromal cells. These data demonstrate that EphA7 identifies a subpopulation of multipotent PCs that have high angiogenesis and regenerative potency and are an attractive target for regenerative therapies., (© 2019 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Ninjurin 1 (Ninj1) is identified as a peripheral nerve injury-induced protein. However, the role of Ninj1 in nerve regeneration is unclear. Schwann cells (SCs) and microvasculature are critical for peripheral nerve regeneration. SCs precursors and microvascular pericytes (PCs), which are nerve/glial antigen 2 (NG2)-positive cells are observed in peripheral nervous system. In this study, we investigated the role of Ninj1 in peripheral nerve regeneration using NG2 + cell-specific inducible deletion of Ninj1 mouse model. The number of NG2 + cells, which were associated with and without microvessels was increased after sciatic nerve crush injury. There was a significant increase in the expression of Ninj1 and EphA7 in the injured nerve tissue. This increase was mostly observed in NG2 + cells. Genetic tracing of NG2 + cells was performed using tamoxifen (Tam) treatment on NG2CreERT:R26R-tdTomato mice. The sciatic nerve was injured following the Tam-treatment, then tdTomato-expressing SCs were mostly observed in regenerated SCs at 21 days after nerve injury. Ninj1 gene knockout (Ninj1 KO) in NG2 + cells was induced using NG2CreERT:Ninj1loxp mice. Tam-treated-NG2CreERT or Tam-nontreated NG2CreERT:Ninj1loxp mice were used as controls. Following Tam-treatment, the sciatic nerve in each group was injured. Ninj1KO significantly attenuated the expression of the myelin binding protein (MBP) as well as the number of myelinated axons. The expression of MBP in cultured SCs was significantly reduced by SiRNA-mediated Ninj1 knockdown (KD). Ninj1KD also attenuated the differentiation of SCs by isolated EphA7 + multipotent PCs. The current data indicate that Ninj1 plays a vital role in peripheral nerve regeneration. This is observed particularly in the myelination process of NG2 + cells including SCs precursors and multipotent PCs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein that controls the cellular response to oxidative stress and possesses DNA-repair functions. It has important roles in the progression and outcomes of various diseases; however, its function and therapeutic prospects with respect to kidney injury are unknown. To study this, we activated APE1 during kidney injury by constructing an expression vector (pCAG-APE1), using an EGFP expression plasmid (pCAG-EGFP) as a control. We performed unilateral ureteral obstruction (UUO) as a model of tubulointerstitial fibrosis on ICR mice before each vector was administrated via retrograde renal vein injection. In this model, pCAG-APE1 injection did not produce any adverse effects and significantly reduced histological end points including fibrosis, inflammation, tubular injury, and oxidative stress, as compared to those parameters after pCAG-EGFP injection. qPCR analysis showed significantly lower expression of Casp3 and inflammation-related genes in pCAG-APE1-injected animals compared to those in pCAG-EGFP-injected UUO kidneys. RNA-Seq analyses showed that the major transcriptional changes in pCAG-APE1-injected UUO kidneys were related to immune system processes, metabolic processes, catalytic activity, and apoptosis, leading to normal kidney repair. Therefore, APE1 suppressed renal fibrosis, not only via antioxidant and DNA-repair functions, but also partly by modulating the immune system through multiple pathways including Il6, Tnf, and chemokine families. Thus, therapeutic APE1 modulation might be beneficial for the treatment of renal diseases.

Many studies have shown that aerobic exercise improves cognitive function and maintains brain health. In particular, moderate-intensity exercise is effective for improving cognitive performance. However, there is no strong consensus on whether a single exercise session improves working memory (WM) function, as it does inhibitory function. It is possible that these discrepancies involve inter-individual differences in WM function. Therefore, we investigated whether acute mild and moderate aerobic exercise improve WM, and whether there exist inter-individual differences in improvements in WM. Thirty healthy subjects were recruited and participated in three experimental conditions (control, mild-intensity exercise, and moderate-intensity exercise). Subjects performed 10 min of exercise on a cycle ergometer with an individualized load. Their pedaling rate was maintained at 60 rpm. In the control condition, subjects rested on the cycle ergometer instead of performing exercise. The N-back task (2-back and 0-back task) was performed to assess WM function before, 5 min, and 15 min after the 10-min exercise session. In this study, to elucidate the effect of an acute bout of mild or moderate exercise on WM, the "2-back- 0-back" contrast, which is assumed to represent WM function, was calculated. The Two-Dimensional Mood Scale was adopted to measure changes in psychological mood states efficiently. The results revealed that working memory function was not improved by acute mild or moderate exercise. However, baseline working memory function was significantly associated with any change in working memory function following exercise, and this was independent of exercise intensity. Subjects with the lowest working memory function at baseline responded the most favorably. The results revealed that improvements in working memory function after a single session of aerobic exercise depend on baseline working memory function., Competing Interests: The authors have declared that no competing interests exist.

Objective- Angiogenesis, entire step from endothelial cells (ECs) sprouts to vascular maturation, is a critical response to ischemia. To form functional mature vessels, interactions between ECs and pericytes are essential. Ninj1 (ninjurin1) is an adhesion molecule that contributes to the pathogenesis of neuroinflammation. We recently demonstrated that Ninj1 is expressed in pericytes during angiogenesis. However, the role of Ninj1 in angiogenesis under pathophysiological ischemic conditions has not yet been elucidated. Approach and Results- Ninj1 was detected in microvessels, and its expression was enhanced in ischemic tissues after mouse hindlimb ischemia. Knockdown of Ninj1 was performed by injection of biodegradable microspheres releasing Ninj1-small interfering RNA into muscle tissues. Alternatively, pericyte-specific Ninj1 knockout was induced by tamoxifen treatment of NG2-CreERT/Ninj1-flox mice. Ninj1 knockdown/knockout reduced the formation of blood-circulating functional vessels among total CD31 + microvessels within ischemic tissues and subsequently attenuated color Doppler-assessed blood flow recovery. Ninj1 overexpression enhanced expression of Anpt (angiopoietin) 1, whereas Ninj1 knockdown enhanced the endogenous Anpt1 antagonist, Anpt2 expression in pericytes and inhibited the association of pericytes with ECs and subsequent formation of capillary-like structure, that is, EC tube surrounded with pericytes in 3-dimensional gel culture. Conclusions- Our data demonstrate that Ninj1 is involved in the formation of functional matured vessels through the association between pericytes and ECs, resulting in blood flow recovery from ischemia. These findings further the current our understanding of vascular maturation and may support the development of therapeutics for ischemic diseases.

Background: Cough peak flow (CPF) is widely used for measuring voluntary cough intensity. However, the respective factors that affect CPF are not known. The aim of this study was to determine the factors affecting CPF by sex in community-dwelling adults., Method: We recruited participants using posters exhibited at a public gymnasium. Participation was voluntary, and all participants provided informed consent. Nonsmoking community residents (102 males, 49.6 ± 20.2 years of age; 101 females, 51.4 ± 18.4 years of age) participated in this study. The main outcome measures were sex differences in CPF, respiratory function, respiratory muscle strength, thorax extension, and grip strength. Factors affecting CPF by sex were analyzed using multiple regression analysis., Results: All parameters were higher in men than in women. CPF was affected by thorax expansion at the tenth rib, inspiratory muscle strength and forced expiration in 1 s in men, and thorax expansion at the tenth rib, inspiratory reserve volume, and expiratory muscle power in women. A weak negative correlation was observed between CPF and age ( p = -0.24, p < 0.05) in women., Conclusions: The factors affecting CPF differed by sex in community-dwelling adults. Clinical Trial Number: UMIN000023912.

Near-infrared spectroscopy (NIRS) can measure cortical activity during gross motor tasks based on the cerebral hemodynamic response. Although some reports suggest that cycling exercise improves cortical oxygenation, its after-effects are unknown. We examined the after-effects of low- and moderate-intensity cycling exercise on cortical oxygenation. Ten healthy volunteers (mean age 21.3 ± 0.7 years; 4 women) underwent cycle ergometer exercise at 30% or 50% of VO 2 peak for 20 min, followed by an 8-min post-exercise rest (PER). O 2 Hb levels of the supplementary motor area (SMA) and sensorimotor cortex (SMC) were recorded using a near-infrared spectroscopy system. Skin blood flow (SBF) and mean arterial pressure (MAP) were continuously measured. The peak values of O 2 Hb between exercise and PER were compared. The O 2 Hb, SBF, and MAP increased in the exercise phase. SBF degraded over time, and MAP decreased immediately after exercise. The O 2 Hb decreased immediately and increased again in the PER. There were no significant differences between exercise and PER in the SMC in the 30% VO 2 peak experiment or in the SMA and SMC in the 50% VO 2 peak experiment. The O 2 Hb in the motor-related area was elevated during both exercise and PER especially in the 50% VO 2 peak experiment.

The present study investigated whether changes in oxyhemoglobin (O 2 Hb) concentration over time differed across brain regions according to differences in gross movement intensity. Thirteen healthy adults (21.2 ± 1.0 years, 8 women) participated in this study. After 180 s of rest, the participants performed 600 s of exercise on a cycle ergometer. Exercise intensity was set at 30%VO 2 peak and 50%VO 2 peak. The prefrontal cortex (PFC) and primary motor cortex (M1) were chosen as regions of interest. In addition, mean arterial pressure (MAP) and scalp blood flow (SBF) were measured simultaneously. O 2 Hb concentration in PFC and M1 was significantly decreased in initial phase of the exercise, while it was significantly increased from the mid to final phase for both intensities compared with resting state values (p < 0.01). The O 2 Hb concentrations in the PFC and M1 were significantly decreased in the initial exercise phase. However, the MAP and SBF values did not exhibit a similar pattern. The main findings of our study were the follows: (1) During cycle ergometer exercise at the 30% and 50% O 2 Hb peak, the after O 2 Hb concentrations were transiently decreased in the initial exercise phase, and the concentrations then steadily increased in both the PFC and M1; and (2) the duration of the transient decreases in the O 2 Hb concentrations varied according to the brain region and exercise intensity.

Acute aerobic exercise at a mild intensity improves cognitive function. However, the response to exercise exhibits inter-individual differences, and the mechanisms underlying these differences remain unclear. The objective of this study was to determine potential factors in the brain that underlie differential responses to exercise in terms of cognitive improvement using functional near-infrared spectroscopy. Fourteen healthy subjects participated in these experiments. Participants performed a low intensity cycling exercise at 30% maximal oxygen uptake (VO 2peak ) for 10 min and performed a spatial memory task before and after exercising (5 and 30 min). The spatial memory task comprised two levels of difficulty (low: 1-dot EXERCISE, high: 3-dot EXERCISE). Cortical oxy-hemoglobin (O 2 Hb) levels were recorded using near-infrared spectroscopy during both the exercise and the spatial memory task phases. Regions of interests included the dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), and frontopolar area (FPA). The participants were divided into two groups depending on whether they were responders (improved task reaction time) or non-responders (no improvement). Subsequently, we analyzed the group characteristics and differences in the change in O 2 Hb levels during exercise and spatial working memory tasks. Acute mild exercise significantly improved mean reaction times in the 1-dot memory task but not in the 3-dot task across the participants. In the 1-dot EXERCISE, 10 subjects were responders and four subjects were non-responders, whereas in the 3-dot EXERCISE, seven subjects were non-responders. In responders, during exercise, we found higher O 2 Hb levels in the right VLPFC response for the 1-dot memory task. Acute mild exercise caused inter-individual differences in spatial memory improvement, which were associated with changes in O 2 Hb activity in the prefrontal area during the exercise phase but not during the actual spatial memory task. Therefore, individuals who respond with higher reactivity to mild intensity exercise in the VLPFC might obtain larger spatial working memory improvements following exercise than non-responders.

Although malnutrition indicates an unfavorable prognosis in some clinical settings, the synergistic impact of nutritional state, renal dysfunction and left ventricular hypertrophy (LVH) on cardiovascular events is unknown. Among 338 patients aged 40-80 years who underwent echocardiographic evaluation between 2003 and 2005, 161 patients who were followed for >7 years were recruited. Malnutrition was defined as a geriatric nutritional risk index (GNRI) of ⩽96. The mean patient age was 63.5±9.2 years; the mean estimated glomerular filtration rate (eGFR) was 72.9±18.7 ml min(-1) per 1.73 m(2); the mean LV mass index was 114±33 g m(-)(2); and the mean GNRI was 100.4±6.0. Among the patients, 25% (n=40) had an eGFR of <60 ml min(-1) per 1.73 m(2), 29% (n=46) exhibited chronic kidney disease (CKD) and 37% (n=59) had LVH. During the follow-up period (median: 96 months), cardiovascular events were observed in 15 patients (9%). Kaplan-Meier curves showed a significantly higher incidence of cardiovascular events in patients with an eGFR of <60 ml min(-1) per 1.73 m(2) (log-rank P=0.007), a GNRI of ⩽96 (P=0.003) or LVH (P=0.010). In a Cox regression analysis, eGFR, LVH and GNRI were independent determinants of cardiovascular event incidence after adjusting for age, gender and the presence of hypertension and diabetes. Furthermore, the combination of LVH and lower GNRI was significantly associated with a higher rate of cardiovascular events not only in all patients but also in patients with CKD. In conclusion, malnutrition, low eGFR and LVH were independent determinants of cardiovascular event incidence; they synergistically increased rates of these events in the long term. The evaluation and management of LVH progression and the improvement of nutritional status are critical for preventing cardiovascular complications even in non-dialysis patients.

Unlabelled: : Overcoming the insufficient survival of cell grafts is an essential objective in cell-based therapy. Apurinic/apyrimidinic endonuclease/redox factor 1 (APE1) promotes cell survival and may enhance the therapeutic effect of engrafted cells. The aim of this study is to determine whether APE1 overexpression in cardiac progenitor cells (CPCs) could ameliorate the efficiency of cell-based therapy. CPCs isolated from 8- to 10-week-old C57BL/6 mouse hearts were infected with retrovirus harboring APE1-DsRed (APE1-CPC) or a DsRed control (control-CPC). Oxidative stress-induced apoptosis was then assessed in APE1-CPCs, control-CPCs, and neonatal rat ventricular myocytes (NRVMs) cocultured with these CPCs. This analysis revealed that APE1 overexpression inhibited CPC apoptosis with activation of transforming growth factor β-activated kinase 1 (TAK1) and nuclear factor (NF)-κB. In the coculture model, NRVM apoptosis was inhibited to a greater extent in the presence of APE1-CPCs compared with control-CPCs. Moreover, the number of surviving DsRed-positive CPC grafts was significantly higher 7 days after the transplant of APE1-CPCs into a mouse myocardial infarction model, and the left ventricular ejection fraction showed greater improvement with attenuation of fibrosis 28 days after the transplant of APE1-CPCs compared with control-CPCs. Additionally, fewer inflammatory macrophages and a higher percentage of cardiac α-sarcomeric actinin-positive CPC-grafts were observed in mice injected with APE1-CPCs compared with control-CPCs after 7 days. In conclusion, antiapoptotic APE1-CPC graft, which increased TAK1-NF-κB pathway activation, survived effectively in the ischemic heart, restored cardiac function, and reduced cardiac inflammation and fibrosis. APE1 overexpression in CPCs may serve as a novel strategy to improve cardiac cell therapy., Significance: Improving the survival of cell grafts is essential to maximize the efficacy of cell therapy. The authors investigated the role of APE1 in CPCs under ischemic conditions and evaluated the therapeutic efficacy of transplanted APE1-overexpressing CPCs in a mouse model of myocardial infarction. APE1 hindered apoptosis in CPC grafts subjected to oxidative stress caused in part by increased TAK1-NF-κB pathway activation. Furthermore, APE1-CPC grafts that effectively survived in the ischemic heart restored cardiac function and attenuated fibrosis through pleiotropic mechanisms that remain to be characterized. These findings suggest that APE1 overexpression in CPCs may be a novel strategy to reinforce cardiac cell therapy., (©AlphaMed Press.)

Objective: Relationship between microalbuminuria and worse outcome of coronary artery disease patients is discussed, but its underlying pathophysiological mechanism remains unclear. We investigated the role of microalbuminuria to the function of endothelial progenitor cells (EPCs), that might affect to outcome of acute myocardial infarction (AMI) patients., Methods: Forty-five AMI patients were divided into two groups according to their urinary albumin excretion: normal (n = 24) and microalbuminuria (>30 mg/day, n = 21). At day-2 and day-7 after AMI onset, circulating-EPCs (CD34+ Flk1+) were quantified by flow cytometry. The number of lectin-acLDL-positive cultured-EPCs immobilized on fibronectin was determined. To assess the cellular senescence of cultured-EPCs, the expression level of sirtuin-1 mRNA and the number of SA-β-gal positive cell were evaluated. Angiographic late in-stent loss after percutaneous coronary intervention (PCI) was evaluated at a six-month follow-up., Results: No significant differences in coronary risk and the extent of myocardial damage were observed between the two groups. Late in-stent loss at the six-month follow-up was significantly higher in the microalbuminuria group (normal:microalbuminuria = 0.76±0.34:1.18±0.57 mm, p=0.021). The number of circulating-EPCs was significantly increased in microalbuminuria group at day-7, however, improved adhesion of EPCs was observed in normal group but not in microalbuminuria group from baseline to day-7 (+3.1±8.3:-1.3±4.4%: p<0.05). On the other hand, in microalbuminuria group at day-7, the level of sirtuin-1 mRNA expression of cultured-EPCs was significantly decreased (7.1±8.9:2.5±3.7 fold, p<0.05), which was based on the negative correlation between the level of sirtuin-1 mRNA expression and the extent of microalbuminuria. The ratio of SA-β-gal-positive cells in microalbuminuria group was increased compared to that of normal group., Conclusions: Microalbuminuria in AMI patients is closely associated with functional disorder of EPCs via cellular senescence, that predicts the aggravation of coronary remodeling after PCI.

Background: Capillary pericytes (cPCs), the mural cells of microvessels, play an important role in the formation and maintenance of microvessels; however, little is known about the mechanisms of how cPCs regulate angiogenesis. To identify factors that modulate cPC function, genes whose levels were altered in cPCs during neovessel formation were identified through a microarray screen., Methods and Results: Ninjurin1 (nerve injury-induced protein, Ninj1) was selected as a candidate factor for angiogenesis regulation. Ninj1 was expressed in capillary cells including endothelial cells (cECs) and was expressed at a higher level in cPCs. Hypoxia induced the gene expression of Ninj1 in addition of vascular endothelial growth factor (VEGF) in cPCs. When cPCs were co-incubated with a thoracic aorta in a three-dimensional Matrigel system, the length of the EC-tubes sprouting from the aorta was increased. Small interfering RNA-mediated downregulation of Ninj1 in cPCs enhanced these cPCs-mediated angiogenic effects, whereas overexpression of Ninj1 attenuated their effects. The production of angiogenic growth factors, such as VEGF and angiopoietin 1, by cPCs was enhanced by the downregulation of Ninj1, and reduced by the overexpression of Ninj1., Conclusions: Ninj1 is a novel regulator for the angiogenic effect of PCs. Specifically, Ninj1 negatively regulates the formation of neovessels, that is, the EC-tube, by reducing the trophic effects of cPCs.

Background: Combination antihypertensive therapy with an angiotensin receptor blocker (ARB) and a calcium channel blocker (CCB) or diuretics is common. This subanalysis investigated blood pressure (BP) variability in patients receiving ARB-based combination therapy., Methods: In a prospective, randomized, open-label trial, hypertensive outpatients (≥65 years) who did not achieve their target BP with ARB monotherapy switched to losartan 50 mg/hydrochlorothiazide 12.5 mg (ARB + D) or ARB plus amlodipine 5 mg (ARB + C) for 12 months. Clinic BP and heart rate (HR), measured every 3 months, visit-to-visit variability and seasonal variation were evaluated., Results: No significant between-group differences in average, maximum, or minimum systolic or diastolic BP, or HR, were found. Visit-to-visit BP variability (systolic) was significantly higher in the ARB + D group than in the ARB + C group. When each group was subdivided into two seasonal groups (summer and winter), no significant between-group differences in BP were found. Multivariate regression analyses showed a tendency toward negative correlation between outdoor temperature and urinary albumin:creatinine ratio and estimated glomerular filtration rate at 12 months in the ARB + D group., Conclusion: Combination therapy with an ARB plus a CCB may be preferable to that with an ARB plus diuretics for decreasing BP variability. As for seasonal variability, both treatments can be used safely regardless of season.