scholarly journals PGC-1α Participates in the Protective Effect of Chronic Intermittent Hypobaric Hypoxia on Cardiomyocytes

2018 ◽  
Vol 50 (5) ◽  
pp. 1891-1902 ◽  
Author(s):  
Shuo Gu ◽  
Hong Hua ◽  
Xinqi Guo ◽  
Zhanfeng Jia ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Protein Expression ◽  
Protein Level ◽  
Hypobaric Hypoxia ◽  
Molecular Mechanisms ◽  
Ventricular Myocytes ◽  
Ischemia Reperfusion ◽  
Sprague Dawley ◽  
Knock Down ◽  
Intermittent Hypobaric Hypoxia

Background/Aims: Myocardial ischemia/reperfusion (I/R) or hypoxia/reoxygenation (H/R) injury is always characterized by Ca2+ overload, energy metabolism disorder and necrocytosis of cardiomyocytes. We showed previously that chronic intermittent hypobaric hypoxia (CIHH) improves cardiac function during I/R through improving cardiac glucose metabolism. However, the underlying cellular and molecular mechanisms of CIHH treatment improving energy metabolism in cardiomyocytes are still unclear. In this study, we determined whether and how CIHH protects cardiomyocytes from Ca2+ overload and necrocytosis through energy regulating pathway. Methods: Adult male Sprague-Dawley rats were randomly divided into two groups: control (CON) and CIHH group. CIHH rats received a hypobaric hypoxia simulating 5,000-m altitude for 28 days, 6 hours each day, in hypobaric chamber. Rat ventricular myocytes were obtained by enzymatic dissociation. The intracellular calcium concentration ([Ca2+]i) and cTnI protein expression were used to evaluate the degree of cardiomyocytes injury during and after H/R. The mRNA and protein expressions involved in cardiac energy metabolism were determined using quantitative PCR and Western blot techniques. PGC-1α siRNA adenovirus transfection was used to knock down PGC-1α gene expression of cardiomyocytes to determine the effect of PGC-1α in the energy regulating pathway. Results: H/R increased [Ca2+]i and cTnI protein expression in cardiomyocytes. CIHH treatment decreased [Ca2+]i (p< 0.01) and cTnI protein expression (p< 0.01) in cardiomyocytes after H/R. Both mRNA and protein expression of PGC-1α increased after CIHH treatment, which was reversed by PGC-1α siRNA adenovirus transfection. Furthermore, CIHH treatment increased the expression of HIF-1α, AMPK and p-AMPK in cardiomyocytes, and pretreatment with AMPK inhibitor dorsomorphin abolished the enhancement of PGC-1α protein expression in cardiomyocytes by CIHH (p< 0.01). In addition, PGC-1α knock down also abolished the increased protein level of GLUT4 (p< 0.01) and decreased the protein level of CPT-1b (p< 0.05) in cardiomyocytes by CIHH treatment. Conclusion: CIHH treatment could reduce the calcium overload and H/R injury in cardiomyocytes by up-regulating the expression of PGC-1α and regulating the energy metabolism of glucose and lipid. The HIF-1α-AMPK signaling pathway might be involved in the process.

The anti-arrhythmic effect of chronic intermittent hypobaric hypoxia in rats with metabolic syndrome induced with fructose

2015 ◽  
Vol 93 (4) ◽  
pp. 227-232 ◽  
Author(s):  
Jing-Jing Zhou ◽  
Hui-Jie Ma ◽  
Yan Liu ◽  
Yue Guan ◽  
Leonid N. Maslov ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Hypobaric Hypoxia ◽  
Ischemia Reperfusion ◽  
Resting Potential ◽  
Sprague Dawley ◽  
Cellular Mechanisms ◽  
Intermittent Hypobaric Hypoxia ◽  
Sprague Dawley Rats ◽  
Phase 0 ◽  
Hypoxia Treatment

This study investigated the anti-arrhythmic effects from chronic intermittent hypobaric hypoxia (CIHH) and the cellular mechanisms in rats with metabolic syndrome. Male Sprague–Dawley rats were randomly distributed among the control, fructose-fed (fed with 10% fructose in the drinking water to induce metabolic syndrome), CIHH (42 days of hypobaric hypoxia treatment simulating an altitude of 5000 m a.s.l.: PB = 404 mm Hg, PO2 = 84 mm Hg, 6 h per day), and the CIHH plus fructose (CIHH-F) groups. In anesthetized rats, the arrhythmia score was determined after 30 min of cardiac ischemia followed by 120 min of reperfusion. Action potentials (AP) were recorded from isolated ventricular papillary muscles. The arrhythmia score was much lower in CIHH-F rats than in the fructose-fed rats. Under basic conditions, AP duration (APD) was significantly shortened in fructose-fed rats, but obviously prolonged in CIHH rats compared with that of the control rats. During ischemia, the AP amplitude, the maximal rate of rise of phase 0, APD, and resting potential, were lower in the control, fructose-fed, and CIHH-F groups, but were not changed in the CIHH rats. The lower AP during ischemia did not recover after washout for the fructose-fed rats. In conclusion, CIHH protects the heart against ischemia–reperfusion induced arrhythmia in rats with metabolic syndrome. This effect of CIHH is possibly related to baseline prolongation of the AP and attenuation of AP reduction during ischemia–reperfusion.

scholarly journals Implication of CREB in the calcium regulation by ischemia/reperfusion in cardiomyocytes

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Débora Falcón ◽  
Isabel Mayoral ◽  
Antonio Ordóñez ◽  
Tarik Smani
Keyword(s):  
Transcription Factor ◽  
Protein Expression ◽  
Molecular Mechanisms ◽  
Ventricular Myocytes ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Expression Of Genes ◽  
Transcription Factor Activation

It is well established that abnormalities in [Ca2+] regulation occur in heart diseases. Actually, independent studies demonstrated that Orai1/2/3 and TRPC protein related with store-operated calcium channels (SOCC) have a role in cardiac pathologies. Ischemia/reperfusion (I/R) stimulates transcription factor activation that modifies the expression of genes implicated in the pathogenesis of this process. Previous results described an increase in the expression of Orai1 and TRPC5 in cardiomyocytes after I/R, although the molecular mechanisms that mediate this regulation are still unknown. The aim of this study is to examine the molecular mechanisms implicated in the regulation of SOCC in cardiomyocytes after I/R focusing on the handling of intracellular [Ca2+]. Experiments were performed in a rat model of myocardial I/R, in adult (ARVM) and neonatal rat ventricular myocytes (NRVM), and in ventricular samples of heart-failure patients. Immunofluorescence was used to investigate CREB activation, and the protein expression was analyzed by Western blot. Calcium diastolic studies were realized using microfluorimetric technic with FURA-2AM. To evoke intracellular Ca2+ transients, ARVMs were field stimulated at 0.5 Hz and NRVMs at 1 Hz. An activation of CREB after I/R was observed in adult and neonatal rat cardiomyocytes. Furthermore, it was demonstrated that this activation was mediated by PKA, but not for EPAC2 or ERK. I/R induced an CREB-dependent ORAI protein expression increase and also an increase in the diastolic calcium in NRVM and ARVM from I/R animal models. Additionally, it was observed that ORAI1 inhibition with SYNTA-66 or GSK reduced the calcium diastolic increase induced by I/R. We demonstrated, for the first time, the activation of the transcription factor CREB in cardiomyocytes after I/R. This activation induces an up-regulation of ORAI1, suggesting that this channel plays a role in the I/R induced calcium diastolic increase.

scholarly journals Effects of Yiqi Tongyang on HCN4 Protein Phosphorylation in Damaged Rabbit Sinoatrial Node Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-6
Author(s):  
Jinfeng Liu ◽  
Ruxiu Liu ◽  
Jie Peng ◽  
Yanli Wang
Keyword(s):  
Protein Expression ◽  
Protein Phosphorylation ◽  
Treatment Effects ◽  
Molecular Mechanisms ◽  
Sinoatrial Node ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Model Group ◽  
Sinoatrial Node Cells

The hyperpolarization-activated cyclic nucleotide-gated cation channel (If) is closely associated with sinoatrial node pacing function. The present study aimed to investigate the molecular mechanisms involved in pacing function improvements of damaged sinoatrial node cells and the consequent treatment effects on sick sinus syndrome (SSS) after the use of Yiqi Tongyang. HCN4 channel protein expression and phosphorylation were measured by immunoblotting and fluorescent quantitation. After ischemia-reperfusion injury (model group), the HCN4 protein and the optical density (OD) of the phosphorylated HCN4 protein as well as intracellular PKA activity in the sinoatrial node cells decreased significantly. However, the OD values and PKA activity increased to different degrees after treatment with serum containing different doses of Yiqi Tongyang; in contrast, no significant improvement was seen in the control group compared to the model group. These findings demonstrated that the use of the traditional Chinese medicine Yiqi Tongyang could increase HCN4 protein expression and phosphorylation as well as PKA activity within sinoatrial node cells damaged by ischemia-reperfusion. The HCN4 protein is involved in theIf-related ion channel. Here, we speculated that these effects could be associated with upregulation of HCN4 protein phosphorylation, which consequently improved cell automaticity, increased heart rate, and had treatment effects on SSS.

Chronic intermittent hypobaric hypoxia decreases β-adrenoceptor activity in right ventricular papillary muscle

2010 ◽  
Vol 298 (4) ◽  
pp. H1267-H1272 ◽  
Author(s):  
Yue Guan ◽  
Lu Gao ◽  
Hui-Jie Ma ◽  
Qian Li ◽  
Hao Zhang ◽  
...  
Keyword(s):  
Action Potential ◽  
Right Ventricular ◽  
Papillary Muscle ◽  
Action Potential Duration ◽  
Adrenergic Receptor ◽  
Hypobaric Hypoxia ◽  
Radioligand Binding ◽  
Ischemia Reperfusion ◽  
Intermittent Hypobaric Hypoxia ◽  
Membrane Bound

Chronic intermittent hypobaric hypoxia (CIHH) has an effective cardiac protection against ischemia-reperfusion injury. However, the underlying mechanisms are not fully known. It has been shown that blockade of β-adrenergic receptor exerts anti-arrhythmic action and improves cardiac remodeling in ischemic myocardium. Thus we determined the influence of CIHH on β-adrenergic receptor activity in right ventricular papillary muscle of rats. We found that the action potential duration in right ventricular papillary muscle was significantly longer in CIHH rats than in control rats. Activation of β-adrenergic receptor with dl-isoproterenol dose-dependently increased action potential duration and the contractility in right ventricular papillary muscle. In CIHH rats, the prolonged effect of dl-isoproterenol on action potential duration and the positive inotropic effect were significantly decreased compared with that in control rats. Furthermore, radioligand-binding experiments revealed that the density and affinity of β-adrenergic receptor in right ventricular myocardium was significantly lower in CIHH rats. In addition, Western blot analysis revealed that the membrane-bound G protein Gsα expression level in cardiac myocardium was significantly lower in CIHH rats than that in control rats. Collectively, these data suggest that CIHH suppresses β-adrenergic receptor action in right ventricular papillary muscle through decreasing receptor density and affinity, as well as membrane-bound Gsα. This mechanism may be involved in the cardiac protective effect of CIHH.

scholarly journals Testosterone enhances estradiol's cardioprotection in ovariectomized rats

2011 ◽  
Vol 212 (1) ◽  
pp. 61-69 ◽  
Author(s):  
Aiying Liu ◽  
Liping Gao ◽  
Shoulei Kang ◽  
Ying Liu ◽  
Chuanying Xu ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Testosterone Replacement ◽  
Ovariectomized Rats ◽  
Sham Operation ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Ovx Rats ◽  
Ldh Release

After menopause, the development of cardiovascular disease (CVD) is due not only to estrogen decline but also to androgen decline. This study examined the effects of either estradiol (E2) or testosterone replacement alone or E2–testosterone combination on isolated myocytes in ovariectomized (Ovx) rats subjected to ischemia/reperfusion (I/R). Furthermore, we determined whether the effects are associated with β2-adrenoceptor (β2-AR). Five groups of adult female Sprague–Dawley rats were used: Sham operation (Sham) rats, bilateral Ovx rats, Ovx rats with E2 40 μg/kg per day (Ovx+E), Ovx rats with testosterone 150 μg/kg per day (Ovx+T), and Ovx rats with E2 40 μg/kg per day+testosterone 150 μg/kg per day (Ovx+E/T). We determined the lactate dehydrogenase (LDH) release, percentage of rod-shaped cells and apoptosis of ventricular myocytes from rats of all groups subjected to I/R. Then, we determined the above indices and contractile function with or without a selective β2-AR antagonist ICI 118 551. We also determined the expression of β2-AR. Our data show that either E2 or testosterone replacement alone or E2 and testosterone in combination decreased the LDH release, increased the percentage of rod-shaped cells, reduced apoptotic cells (%), and combination treatment appeared to be more effective than either E2 or testosterone replacement alone. ICI 118 551 abolished the effects of the three. Combination supplementation also enhanced the expression of β2-AR. We concluded that in Ovx rats, testosterone enhances E2's cardioprotection, while E2 and testosterone in combination was more effective and the protective effects may be associated with β2-AR. The study highlights the potential therapeutic application for CVD in postmenopausal women.

Effect of N-Acetylserotonin on TLR-4 and MyD88 Expression during Intestinal Ischemia-Reperfusion in a Rat Model

2018 ◽  
Vol 29 (02) ◽  
pp. 188-195 ◽  
Author(s):  
Yoav Ben Shahar ◽  
Salim Halabi ◽  
Nir Bitterman ◽  
Tatiana Dorfman ◽  
Yulia Pollak ◽  
...  
Keyword(s):  
Protein Expression ◽  
Intestinal Mucosa ◽  
Intestinal Ischemia ◽  
Structural Changes ◽  
Ischemia Reperfusion ◽  
Mucosal Injury ◽  
Mucosal Damage ◽  
Sprague Dawley ◽  
Gene And Protein Expression ◽  
Intestinal Ischemia Reperfusion

Background Accumulating evidence indicates that changes in intestinal toll-like receptors (TLRs) precede histological injury in a rodent model of necrotizing enterocolitis. N-acetylserotonin (NAS) is a naturally occurring chemical intermediate in the biosynthesis of melatonin. A recent study has shown that treatment with NAS prevents gut mucosal damage and inhibits programmed cell death following intestinal ischemia-reperfusion (IR). The objective of this study was to determine the effects of NAS on TLR-4, myeloid differentiation factor 88 (Myd88), and TNF-α receptor-associated factor 6 (TRAF6) expression in intestinal mucosa following intestinal IR in a rat. Materials and Methods Male Sprague-Dawley rats were randomly assigned to one of the four experimental groups: 1) Sham rats underwent laparotomy; 2) Sham-NAS rats underwent laparotomy and were treated with intraperitoneal (IP) NAS (20 mg/kg); 3) IR rats underwent occlusion of both superior mesenteric artery and portal vein for 20 minutes followed by 48 hours of reperfusion; and 4) IR-NAS rats underwent IR and were treated with IP NAS immediately before abdominal closure. Intestinal structural changes, mucosal TLR-4, MyD88, and TRAF6 mucosal gene, and protein expression were examined using real-time PCR, Western blot, and immunohistochemistry. Results Significant mucosal damage in IR rats was accompanied by a significant upregulation of TLR-4, MyD88, and TRAF6 gene and protein expression in intestinal mucosa compared with control animals. The administration of NAS decreased the intestinal injury score, inhibited cell apoptosis, and significantly reduced the expression of TLR-4, MyD88, and TRAF6. Conclusion Treatment with NAS is associated with downregulation of TLR-4, MyD88, and TRAF6 expression along with a concomitant decrease in intestinal mucosal injury caused by intestinal IR in a rat.

TNF-α-dependent bilateral renal injury is induced by unilateral renal ischemia-reperfusion

2002 ◽  
Vol 282 (2) ◽  
pp. H540-H546 ◽  
Author(s):  
Kirstan K. Meldrum ◽  
Daniel R. Meldrum ◽  
Xianzhong Meng ◽  
Lihua Ao ◽  
Alden H. Harken
Keyword(s):  
Protein Expression ◽  
Renal Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Renal Ischemia ◽  
Sprague Dawley ◽  
Serum Samples ◽  
Contralateral Kidney ◽  
Mrna Induction ◽  
Tnf Α

While tumor necrosis factor (TNF)-α is an important mediator of renal ischemia-reperfusion (I/R) injury, its role in contralateral renal injury after isolated renal ischemia remains unknown. We therefore investigated the effect of isolated left renal ischemia on the nonischemic contralateral kidney. To study this, male Sprague-Dawley rats were anesthetized and exposed to varying degrees of left renal I/R injury. Both kidneys were subsequently harvested, serum samples were obtained, and TNF-α protein expression (ELISA), TNF-α mRNA content (RT-PCR), TNF-α immunolocalization, and neutrophil infiltration (myeloperoxidase assay) were determined. The effect of TNF-α on neutrophil infiltration was assessed by neutralizing TNF-α with TNF binding protein (TNF-BP) before left renal I/R injury. TNF-α protein expression, TNF-α mRNA induction, and neutrophil infiltration increased significantly in both kidneys after unilateral renal I/R injury. Furthermore, the administration of TNF-BP before unilateral renal I/R substantially reduced the degree of neutrophil infiltration bilaterally. These results constitute the initial demonstration that unilateral renal I/R induces bilateral TNF-α production and neutrophil infiltration through a TNF-α-dependent mechanism.

Short-term exercise preserves myocardial glutathione and decreases arrhythmias after thiol oxidation and ischemia in isolated rat hearts

2011 ◽  
Vol 111 (6) ◽  
pp. 1751-1759 ◽  
Author(s):  
Chad R. Frasier ◽  
Ruben C. Sloan ◽  
Phillip A. Bostian ◽  
Michael D. Gonzon ◽  
Jennifer Kurowicki ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Ventricular Myocytes ◽  
Reductase Activity ◽  
Ischemia Reperfusion ◽  
Treadmill Running ◽  
Thiol Oxidation ◽  
Sprague Dawley ◽  
Short Term ◽  
Rat Hearts ◽  
Glutathione Reductase Activity

The purpose of this study was to determine if exercise (Ex) protects hearts from arrhythmias induced by glutathione oxidation or ischemia-reperfusion (I/R). Female Sprague-Dawley rats were divided into two experimental groups: sedentary controls (Sed) or short-term Ex (10 days of treadmill running). Twenty-four hours after the last session, hearts were excised and exposed to either perfusion with the thiol oxidant diamide (200 μM) or global I/R. Ex significantly delayed the time to the onset of ventricular arrhythmia after irreversible diamide perfusion. During a shorter diamide perfusion protocol with washout, Ex significantly decreased the incidence of arrhythmia, as evidenced by a delayed time to the first observed arrhythmia, lower arrhythmia scores, and lower incidence of ventricular fibrillation. Ex hearts exposed to I/R (30-min ischemia/30-min reperfusion) also showed lower arrhythmia scores and incidence of ventricular fibrillation compared with Sed counterparts. Our finding that Ex protected intact hearts from thiol oxidation was corroborated in isolated ventricular myocytes. In myocytes from Ex animals, both the increase in H2O2 fluorescence and incidence of cell death were delayed after diamide. Although there were no baseline differences in reduced-to-oxidized glutathione ratios (GSH/GSSG) between the Sed and Ex groups, GSH/GSSG was better preserved in Ex groups after diamide perfusion and I/R. Myocardial glutathione reductase activity was significantly enhanced after Ex, and this was preserved in the Ex group after diamide perfusion. Our results show that Ex protects the heart from arrhythmias after two different oxidative stressors and support the hypothesis that sustaining the GSH/GSSG pool stabilizes cardiac electrical function during conditions of oxidative stress.

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