bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic Hypoxia Attenuates Endothelium‐dependent Hyperpolarization‐induced Vascular Relaxation in Pulmonary Artery and Leads to Pulmonary Hypertension
Authors: Zhang Qian , Varghese Mathews Valuparampil , Si Rui , Tsuji‐Hosokawa Atsumi , Watanabe Makiko , Hosokawa Susumu , Wang Jian , Makino Ayako 
Published: June 2021

Endothelial cell dysfunction is implicated in the development and progression of many cardiovascular diseases including pulmonary hypertension (PH). It has been well documented that endothelium‐dependent relaxation (EDR) is attenuated due to decreased NO bioavailability in pulmonary artery (PA) of PH model animals; however there is few report investigating the role of endothelium‐dependent hyperpolarization (EDH)‐mediated vascular relaxation in PH. In this study, we examined the role of chronic hypoxia on EDH‐induced pulmonary arterial relaxation with a special focus on connexin 40 (Cx40). Connexins are a group of membrane proteins that form gap junctions between the cells and serve as a tunnel during electrical propagation (e.g., hyperpolarization). Cx40 is predominantly expressed in vascular endothelial cells (ECs). We first examined vasorelaxant properties in the different size of PAs dissected from wild type (Wt) and Cx40 knockout (KO) mice. There was no difference of acetylcholine (ACh)‐induced relaxation (i.e., EDR) in second order of PAs between Wt mice and Cx40 KO mice, while EDR was significantly attenuated in the fourth order of PAs of Cx40 KO mice compared to the Wt mice. In the second order of PAs, we did not observe EDH‐dependent vascular relaxation in both Wt and Cx40 KO mice. In the fourth order of PAs, strong EDH‐dependent relaxation was observed in Wt mice and it was significantly reduced in Cx40 KO mice. Cx40 KO mice exhibited a significant increase in right ventricle systolic pressure (RVSP) compared to Wt mice. Chronic hypoxia (10% O2, 4 weeks) increased RVSP in both Wt and Cx40 KO mice and Cx40 KO mice exposed to hypoxia exhibited significantly higher RVSP than Wt mice exposed to hypoxia. Furthermore, chronic hypoxia attenuated EDR and EDH‐dependent relaxation in the fourth order of PAs from Wt mice; however, there was no difference of EDR and EDH‐dependent relaxation in the fourth order of PAs in Cx40 KO mice. Mouse pulmonary endothelial cells isolated from hypoxia‐exposed Wt mice exhibited significant decrease in Cx40 protein level compared to Wt mice exposed to normoxia. These data suggest that chronic hypoxia decreases Cx40 protein expression and attenuates EDH in small PAs that subsequently leads to increase in pulmonary arterial resistance and develops pulmonary hypertension.Support or Funding InformationNIH R01HL115578This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Increased Glycolysis Contributes to Pulmonary Vascular Remodeling via ERK‐dependent Calpain Activation in Pulmonary Arterial Hypertension
Authors: Kovacs Laszlo , Cao Yapeng , Han Weihong , Meadows Louise , Kovacs‐Kasa Anita , Verin Alexander , Barman Scott , Huo Yuqing , Su Yunchao 
Published: June 2021

Pulmonary arterial hypertension (PAH) is a life‐threatening lung disease which is characterized by pulmonary vascular remodeling due to the abnormal proliferation of vascular smooth muscle cell (SMCs) and overproduction of extracellular matrix (ECM) proteins including collagen. It has been shown that a number of growth factors such as platelet‐derived growth factor (PDGF) as well as the metabolic shift in energy production from oxidative phosphorylation to glycolysis participate in PAH in animal models and patients. We recently reported that calpain mediates collagen synthesis and proliferation of pulmonary arterial SMCs (PASMCs) contributing to the pathogenesis of PAH. The aim of this study is to investigate the mechanisms by which glycolytic shift induces calpain activation in PAH. PASMCs were incubated with PDGF‐BB (10 ng/ml) for 24 h, after which protein content of 6‐Phosphofructo‐2‐kinase/fructose‐2, 6‐bisphosphatase 3 (PFKFB3) and lactate concentration in the cell lysates and in the culture medium were measured. We found that PDGF‐BB significantly increases the protein levels of PFKFB3 and the lactate production. Our results also showed that inhibition of PFKFB3 attenuates PDGF‐induced calpain activity, collagen synthesis and proliferation of PASMCs. Treatment of PASMCs with lactate markedly increased the activities of calpain and extracellular signal–regulated kinase (ERK) without affecting the protein levels of calpain‐1, calpain‐2 and calpastatin in PASMCs suggesting that it may regulate the calpain activity via posttranslational mechanism. Moreover, inhibition of calpain‐2, but not calpain‐1, attenuates the lactate‐induced collagen synthesis and proliferation of PASMCs. In addition, pre‐treatment of the PASMCs with ERK 1/2 inhibitor PD98059 diminishes increases in calpain‐2 phosphorylation at serine 50, collagen synthesis and proliferation of PASMCs induced by lactate. More importantly, pharmacological inhibition of ERK 1/2 by PD98059 attenuates the progression of Sugen/Hypoxia‐induced pulmonary hypertension and pulmonary vascular remodeling in rats. In summary, we have demonstrated that ERK‐stimulated calpain signaling is a critical pathway in PAH which mediates cell proliferation and collagen synthesis in pulmonary vascular smooth muscle cells via enhanced glycolysis.Support or Funding InformationSupported by NIH (YS), Department of Veterans Affairs (YS), FAMRI (YS) and AHA (LK).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of G protein‐coupled estrogen receptors in pulmonary hypertension
Authors: Wolfel Logan C. , Detweiler Neil D. , Cross Laura Weise , Hathaway Helen J. , Jernigan Nikki L. , Prossnitz Eric R. , Resta Thomas C. , Snow Jessica B. 
Published: June 2021

Chronic hypoxia (CH) resulting from chronic obstructive pulmonary disease, sleep apnea, and high altitude exposure leads to oxidative stress and increased pulmonary vascular resistance. The resultant pulmonary hypertension (PH) contributes to right ventricular hypertrophy and may culminate in right heart failure, peripheral edema, and dyspnea. Because the G protein‐coupled estrogen receptor (GPER) has been implicated in oxidative stress in systemic hypertension, we hypothesized that GPER contributes to the development of CH‐induced PH. To test this hypothesis, we assessed indices of PH in female wild type (WT) and GPER knockout (KO) mice exposed to normoxia or CH (4 wk, PB= 0.5 atm) (n= 4–6/group). Right ventricular systolic pressure (RVSP) was measured by direct cardiac puncture during isoflurane anesthesia. In addition, right ventricular hypertrophy and polycythemic responses to CH were determined from Fulton's index (right ventricle/(left ventricle + septum weight)) and hematocrit, respectively. CH resulted in greater RVSP in WT mice (p<0.05), indicative of PH. Although CH also tended to increase Fulton's index and hematocrit in WT mice, these responses did not reach statistical significance. GPER KO mice unexpectedly showed significantly (p < 0.05) elevated RVSP, right ventricular hypertrophy and hematocrit compared to WT controls under normoxic conditions. Furthermore, these responses to GPER knockdown were not potentiated by CH. We conclude that GPER deficiency results in PH under normoxic conditions, supporting a role for GPER in the maintenance of the pulmonary circulation as a low‐pressure circuit.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Ryanodine Receptor 1 mRNA Expression is Increased by Post‐Natal Maturation and Long Term Hypoxia in Sheep Pulmonary Arteries
Authors: Murray Samuel , Dasgupta Chiranjib , Zhang Lubo , Wilson Sean M. 
Published: June 2021

Ryanodine receptors (RyRs) are well regarded for being important to vasorelaxation that occurs during the birth transition and with hypoxic pulmonary vasoconstrictor responses. Previous studies from our group show that RyR mediated Ca2+ spark events are suppressed in fetal pulmonary arterial myocytes and that these events are significantly modified by exposure to long term high altitude hypoxia. To begin to resolve the molecular underpinnings of these physiological responses we performed quantitative real time PCR for mRNA expression of the RyR1 isoform, which is one of three relevant isoforms that are likely to be expressed in pulmonary arterial myocytes. Pulmonary arterial (PA) segments were isolated from near‐term fetal or adult sheep housed at low altitude (300m) or exposed to high altitude (3,801m) for over 100 days. Comparisons of RyR1 mRNA expression were then made to the housekeeping gene beta‐actin. Based on these preliminary studies we found that the ΔCt for RyR1 mRNA expression relative to beta actin was significantly lower in the fetus relative to the adult independent of altitude. The ΔΔCt corresponded to a 12–17 fold increase in RyR1 mRNA expression due to maturation, which potentially accounts for previously shown maturational related enhancements in Ca2+ spark activity. Altitude caused a 2.8 fold increase in RyR1 mRNA expression in adult PA that correlate with previously shown maturational induced increases in spark activity. Interestingly, a 3.8 fold increase in RyR1 mRNA expression observed in fetal PA following hypoxia did not correspond to the hypoxia‐related depression in Ca2+ spark activity that we previously reported. Overall, these preliminary studies show pronounced changes in RyR1 mRNA expression that are likely to be important drivers of pulmonary vascular development as well as underlie pathologies due to long term high altitude exposure.Support or Funding InformationThis work is supported by The National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development grant number HD083132 and HD069746.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Differential Respiratory Response of Isolated Cardiac Mitochondria from Young and Aged Mice towards Nitric Oxide Synthase Inhibitors
Authors: Sakamuri Siva SVP. , Sure Venkata NLR. , Sperling Jared A. , Mahalingam Padmini S. , Dholakia Monica H. , Evans Wesley R. , Katakam Prasad VG. 
Published: June 2021

Mitochondrial respiratory dysfunction is proposed to be an important underlying mechanism in the aging‐induced cardiac abnormalities. Identifying the mechanisms involved in the development of aging‐induced respiratory dysfunction in cardiac mitochondria could be useful to develop therapeutic strategies to reduce the risk of developing cardiovascular diseases. Role of mitochondrial nitric oxide synthase (NOS) to aging‐induced respiratory changes in cardiac mitochondria are not studied previously. Here we treated the isolated cardiac mitochondria from young (3 months) and old mice (18 months) hearts with neuronal NOS inhibitor (nNOS, ARL 17477 dihydrochloride or ARL) and endothelial NOS inhibitor (eNOS, N5‐(1‐Iminoethyl)‐L‐ornithine or NIO) and studied the respiratory characteristics using Seahorse Xfe24 analyzer.ResultsMitochondria from the old mice hearts exhibited significantly increased basal respiration (24.7%, 169.0±14.0 vs 135.5±5.1, p≤0.05) with unchanged ATP production. They also showed a significant decrease in state IIIu respiration (23%, 635.4±40.2 vs 826.4±49.2, p≤0.05) and also the membrane potential. Both ARL and NIO treatments significantly decreased state IIIu respiration (22.1%, 643.7±34.4 vs 826.4±49.2, p≤0.05 & 23.9%, 448±18.5 vs 587.1±34.8, p≤0.05 respectively) in mitochondria from young mice hearts without affecting membrane potential and oxidative stress parameters. Interestingly, ARL and NIO neither induced similar responses in the mitochondria from the old mice hearts nor they corrected the aging‐induced decline in state IIIu respiration and membrane potential. Mitochondria from the old mice hearts have increased nNOS protein levels (421%, 1.98±0.80 vs 0.38±0.20, p≤0.05) with decreased protein S‐nitrosylation (46.25%, 8.3±1.5 vs 15.44±3.2, p≤0.07). The observed differential respiratory responses of cardiac mitochondria from young and old mice following nNOS and eNOS inhibitors were associated with reduced protein S‐nitrosylation in mitochondria from young mice hearts (64.2%, 5.53±0.35 vs 15.44±3.2, p≤0.05 & 65.7%, 5.3±0.84 vs 15.44±3.2, p≤0.05 respectively) with unaltered nitrosylation in mitochondria from old mice hearts.ConclusionsThus the functional loss of mitochondrial nNOS and eNOS in the aged hearts accompanied by the reduced NO‐mediated regulation of mitochondrial proteins contributes to the aging‐induced mitochondrial dysfunction.Support or Funding InformationAmerican Heart Association (PVG: 14SDG20490359 and VNS: 16PRE31450006) and National Institute of Health: National Institute of Neurological Disorders and Stroke and National Institute of General Medical Sciences (PVK: R01NS094834).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Contraction and Relaxation Coupling Unaffected by Disease in Canine and Human Myocardium
Authors: Santini Jorge , Repas Steven J. , Canan Benjamin D. , Billman George E. , Kilic Ahmet , Whitson Bryan , Janssen Paul M.L 
Published: June 2021

In healthy rodent isolated ventricular myocardium, a strong positive correlation (R2>0.95) has been observed between the rate of contraction versus rate of relaxation. Additionally, this correlation remains when muscles are stimulated to contract at different length, different frequency and various levels of beta‐adrenergic stimulation. However, there are drastic differences in EC coupling in small rodents versus larger mammals, including humans. Human and other large mammals, such as dogs, have a much wider range (~10 fold) of modulation of cardiac force and kinetics, thus it is unclear if a contraction‐relaxation coupling exists in larger mammals. In addition, it is unknown if such a relationship would be effected by disease. In this study, we investigated whether there is a correlation between maximal speed of contraction (dF/dt) and relaxation (‐dF/dt) in normal and exercise trained canines, with or without a myocardial infarction, as well as in normal human non‐failing, failing ischemic and failing non‐ischemic myocardium. Preliminary analysis on n=42 canines and N=54 humans suggests that there is a tight coupling between the maximal speed of contraction and relaxation in normal canine (R2=0.99) and non‐failing human myocardium (R2=0.99), with nearly identical slopes of this correlation. Additionally, within exercise or diseased hearts, there is no significant change with this correlation or slope of contraction‐relaxation coupling. We conclude that contraction‐relaxation coupling is a fundamental property that is unaffected by physiological contractile regulatory mechanisms.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Exosomal MicroRNA‐27a Passenger Strand Was Upregulated in Chronic Heart Failure
Authors: Tian Changhai , Gao Lie , Zucker Irving H. 
Published: June 2021

Under cardiac stress, the heart undergoes extensive cardiac remodeling that results in cardiac fibrosis and hypertrophy, which contribute to chronic heart failure (CHF). Data from our lab revealed that microRNA‐27a contributes to the Nrf2 translational inhibition in cardiomyocytes through the communication with cardiac fibroblast‐derived exosomes. Interestingly, microRNA‐27a passenger strand (also call microRNA‐27a*) in infarcted cardiac tissues and extracellular exosomes shows a relatively high abundance which normally undergoes intracellular degradation (Figure. 1). However, the role of microRNA‐27a* in the onset and progression of CHF remains unclear. A bioinformatics analysis using TargetScan software revealed that PDZ and LIM domain 5 (PDLIM5) is one of potential targets of miroRNA‐27a*, and cardiomyocyte‐specific PDLIM5 knock‐out mice have been shown to develop cardiomyopathy, suggesting that PDLIM5 plays a major role in cardiac muscle structure and function, and may contribute to the progression of cardiomyocyte hypertrophy. Thus, we hypothesize that microRNA‐27a* may regulate PDLIM5 through exosomal communication with cardiomyocytes in chronic heart failure. Using western blotting analysis, we demonstrate down‐regulation of PDLIM5 in the infarcted heart compared to normal heart (Figure. 2), which correlated with the alterations of microRNA‐27a* in both of infarcted heart tissue and plasma. Additionally, our in vitro cell culture studies demonstrate that extracellular exosomes secreted by angiotensin II‐treated cardiac fibroblasts enriched abundant microRNA‐27a*, which promoted hypertrophic gene expression in cardiomyocytes. These findings suggest that exosomal microRNA‐27a* secreted by cardiac fibroblasts in response to cardiac stress, may act as a paracrine signaling mediator of cardiomyocyte remodeling that has potential as a therapeutic target and one of diagnostic markers.Support or Funding InformationThis work was supported by National Institutes of Health National Heart, Lung, and Blood Institute grant PO1 HL 62222 (IHZ)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Association between cardio‐metabolic risk factors, plasma catecholamines and cognitive performance in Mexican pre‐adolescents
Authors: Soto‐Piña Alexandra Estela , Flores‐Reséndiz Constantino , Valdés‐Ramos Roxana , Benítez‐Arciniega Alejandra Donají , Martínez‐Carrillo Beatriz 
Published: June 2021

Cardiovascular and metabolic syndrome (MS) risk factors are associated with the generation of vascular cognitive impairment and aging. Dislipidemia and obesity are two of the main factors that promote cognitive decline because of the accumulation of fat in vascular tissue and neuroendocrine disruption. In order to prevent the development of these alterations into chronic diseases, it is important to identify and correct them at earlier life stages. The hypothesis of this study was that metabolic risk factors and sympathoadrenal alterations in pre‐adolescents are associated with cognitive dysfunction. Our aim was to determine whether there is a correlation between cardio‐metabolic risk factors, plasma catecholamines as well as memory, attention and executive functions. We performed a cross‐sectional study where 139 pre‐adolescents 10–14 years old were involved. Memory, attention and executive functions were evaluated using Neuropsi test. Blood concentrations of Triacylglycerols (TG), cholesterol, low density lipoprotein‐cholesterol (LDL‐c), very low lipoprotein‐cholesterol (VLDL‐C), high density lipoprotein cholesterol (HDL‐C) and plasma catecholamines were measured as well. Pearson correlation and multivariate regression analyses were performed to find a relation between these variables. We found that TG and VLDL‐C were negatively related to memory (−0.19 and −0.19, respectively; *p<0.05,). Multivariate regression analysis for memory and executive functions showed that each one has a negative relation with HDL‐c (B= −1.12 and −0.8, respectively; *p<0.05). Moreover, plasma epinephrine was inversely related to executive functions (B=−0–05; *p<0.05). Therefore, elevations of LDL‐c, TG and epinephrine as well as low HDL‐c blood concentrations can alter cognitive performance during pre‐adolescence.Support or Funding InformationThis investigation was supported by grants 3838/2014FSH and 3561/2015PIC from Universidad Autónoma del Estado de México.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Senescence in Myoblasts; Role in Age‐Related Muscle Dysfunction
Authors: Shigdar Shahjahan , Staunton Caroline , Vasilaki Aphrodite , McArdle Anne 
Published: June 2021

Loss of skeletal muscle mass and function are critical factors in the development of frailty although the mechanisms by which this loss occurs are poorly understood. The number of senescent cells increases with age in rodents (Krishnamurthy et al., 2004) and primates (Kreiling et al., 2011) and it is proposed that the presence of these cells plays a role in age‐related muscle dysfunction. We hypothesise that resident satellite cells become senescent and exert detrimental effects on mature muscle fibres via the senescence associated secretory phenotype molecules (SASP).Initial studies have investigated whether a C2C12 mouse muscle myoblast cell line could be induced into senescence, whether key senescence associated molecules (such as p16, p21, and p53) are upregulated and determined the nature of the SASP.C2C12 myoblasts were treated for 24 hours with the topoisomerase II inhibitor, Etoposide, to cause DNA damage. Myoblasts were examined for up to 5 days following treatment for cell viability, Senescence Associated β‐Galactosidase (SAβ‐Gal) activity, immunocytochemistry and western blot analysis for p16, p21, and p53.Treated myoblasts exhibited a significantly altered morphology consistent with a senescence phenotype, increased SAβ‐Gal activity, and cyclin‐dependent kinase inhibitor levels compared with untreated cells.These data suggest that myoblasts can be induced into a senescent phenotype. Further work will characterise the SASP of the cells and determine the effect on mature myotubes co‐cultured with senescent myoblasts.Support or Funding InformationWork generously funded by the British Society for Research into Ageing and the Rosetrees Trust.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.