Hydrogen Sulfide Alleviates Acute Myocardial Ischemia Injury by Modulating Autophagy and Inflammation Response under Oxidative Stress

This study aims to investigate the influence of excessive oxidative stress on cardiac injury during acute myocardial ischemia (AMI), with a focus on apoptosis, autophagy, and inflammatory cell infiltration, and to detect the role of hydrogen sulfide (H2S) in this process. We found that SOD1 knockout (KO) mice showed excessive oxidative stress and exacerbated myocardium injury after AMI. Increased apoptosis and inflammation response in the ischemic myocardium contribute to this deterioration, whereas enhanced autophagy plays a protective role. Myocardial inflammation after AMI was much more severe in SOD1 KO mice than in wild-type mice. Pretreatment with the H2S donor NaHS reduced autophagy and apoptosis levels in the ischemic myocardium and alleviated the regional inflammation response in the cardiac tissues of SOD1 KO mice. Moreover, autophagy and apoptosis levels were significantly enhanced in SOD1 knockdown primary neonatal rat cardiomyocytes (NRCMs) under glucose deprivation. Pretreatment with NaHS can partially inhibit this elevation. Taken together, we found that excessive oxidative stress can aggravate cardiac injury during AMI. Exogenous H2S can alleviate cardiac injury during AMI by reducing apoptosis and inflammation response in heart tissues under oxidative stress.

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Abstract 72: Hydrogen Sulfide Prevents Myocardial Hypertrophy in a Klf5-dependent Manner

Circulation Research ◽

10.1161/res.117.suppl_1.72 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Guoliang Meng ◽

Liping Xie ◽

Yong Ji

Keyword(s):

Oxidative Stress ◽

Hydrogen Sulfide ◽

Promoter Activity ◽

Myocardial Hypertrophy ◽

Neonatal Rat ◽

Cardiomyocyte Hypertrophy ◽

Dependent Manner ◽

Ang Ii ◽

Rat Cardiomyocytes ◽

Neonatal Rat Cardiomyocytes

Rationale: H 2 S is a gasotransmitter that regulates multiple cardiovascular functions. Krüppel-like transcription factor (KLF) exerts diverse functions in the cardiovascular system. Objectives: The aim of present study was to investigate the effect of hydrogen sulfide (H 2 S) on myocardial hypertrophy. Methods and results: Myocardial samples of 22 patients with left ventricle hypertrophy were collected and underwent histological and molecular biological analysis. Spontaneously hypertensive rats (SHR) and neonatal rat cardiomyocytes were studied for functional and signaling response to GYY4137, a H 2 S-releasing compound. Expression of cystathionine -lyase (CSE), a main enzyme for H 2 S generation in human heart, decreased in human hypertrophic myocardium, while KLF5 expression increased. In SHR treated with GYY4137 for 4 weeks, myocardial hypertrophy was inhibited as evidenced by improvement in cardiac structural parameters, heart mass index, size of cardiac myocytes and expression of atrial natriuretic peptide (ANP). Levels of oxidative stress and phosphorylation of mitogen-activated protein kinases were also decreased after H 2 S treatment. H 2 S diminished expression of the KLF5 in myocardium of SHR and in neonatal rat cardiomyocytes rendered hypertrophy by angiotensin II (Ang II). H 2 S also inhibited ANP promoter activity and ANP expression in Ang II-induced neonatal rat cardiomyocyte hypertrophy, and these effects were suppressed by KLF5 knockdown. KLF5 promoter activity was increased by Ang II stimulation, and this was reversed by H 2 S. H 2 S also decreased activity of specificity protein-1 (SP-1) binding to the KLF5 promoter and attenuated KLF5 nuclear translocation by Ang II stimulation. Conclusion: H 2 S attenuated myocardial hypertrophy, which might be related to inhibiting oxidative stress and decreasing ANP transcription activity in a KLF5-dependent manner.

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Thymoquinone Attenuates Myocardial Ischemia/Reperfusion Injury Through Activation of SIRT1 Signaling

Cellular Physiology and Biochemistry ◽

10.1159/000490216 ◽

2018 ◽

Vol 47 (3) ◽

pp. 1193-1206 ◽

Cited By ~ 9

Author(s):

Yunyang Lu ◽

Yingda Feng ◽

Dan Liu ◽

Zhiran Zhang ◽

Kai Gao ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Ischemia ◽

Signaling Pathway ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Cardioprotective Effect ◽

Neonatal Rat ◽

Rat Cardiomyocytes ◽

Production Of Hydrogen ◽

Myocardial Ischemia Reperfusion

Background/Aims: Myocardial ischemia/reperfusion (MI/R) injury is a leading factor responsible for damage in myocardial infarction, resulting in additional injury to cardiac tissues involved in oxidative stress, inflammation, and apoptosis. Thymoquinone (TQ), the main constituent of Nigella sativa L. seeds, has been reported to possess various biological activities. However, few reports regarding myocardial protection are available at present. Therefore, this study was conducted aiming to investigate the protective effect of TQ against MI/R injury and to clarify its potential mechanism. Methods: MI/R injury models of isolated rat hearts and neonatal rat cardiomyocytes were established. The Langendorff isolated perfused heart system, triphenyltetrazolium chloride staining, gene transfection, TransLaser scanning confocal microscopy, and western blotting were employed to evaluate the cardioprotection effect of TQ against MI/R injury. Results: Compared with the MI/R group, TQ treatment could remarkably improve left ventricular function, decrease myocardial infarct size and production of lactate dehydrogenase (LDH), and attenuate mitochondrial oxidative damage by elevating superoxide dismutase (SOD) activity and reducing production of hydrogen peroxide (H2O2) and malonaldehyde (MDA). Moreover, the cardioprotective effect of TQ was accompanied by up-regulated expression of SIRT1 and inhibition of p53 acetylation. Additionally, TQ treatment could also enhance mitochondrial function and reduce the number of apoptotic cardiomyocytes. Nonetheless, the cardioprotective effect of TQ could be mitigated by SIRT1 inhibitor sirtinol and SIRT1 siRNA, respectively, which was achieved through inhibition of the SIRT1 signaling pathway. Conclusions: The findings in this study demonstrate that TQ is efficient in attenuating MI/R injury through activation of the SIRT1 signaling pathway, which can thus reduce mitochondrial oxidative stress damage and cardiomyocyte apoptosis.

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Heparin from Intestine and Lung Source Administered in Large Dose to Dogs with Acute Myocardial Ischemia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648674 ◽

1978 ◽

Vol 40 (02) ◽

pp. 407-417

Author(s):

Michael J Saliba ◽

Richard J Pavalec

Keyword(s):

Coronary Artery ◽

Myocardial Ischemia ◽

Adenosine Triphosphate ◽

Intestinal Mucosa ◽

Large Dose ◽

Acute Myocardial Ischemia ◽

Ischemic Myocardium ◽

Atp Levels ◽

Initial Control ◽

The Difference

SummaryIntestinal mucosa heparin (IMH) and beef lung heparin (BLH) were infused into dogs subjected to myocardial ischemia by intermittent coronary artery occlusions. The IMH was from a mixture of beef, sheep, and pig intestinal mucosa. Initial control occlusion and recovery was followed by a second occlusion with 60,000 units of IMH or BLH added. Electrocardiographic S-T segment elevations (ST) were measured acutely. There were no significant differences in ST in non-ischemic myocardium before occlusions or with occlusions. In ischemic myocardium, IMH significantly lowered control ST 84% in amount (t = 6.1 p <0.00005), and 76% in number (t = 11.6 p <0.00001). BLH lowered control ST a significant, lesser, 36% in amount (t = 3.6 p <0.008), and 35% in number (t = 3.2 p <0.01). The difference between IMH and BLH in ischemic myocardium was a significant 48% in amount (t = 4.0 p <0.0007), and 41% in number (t = 2.0 p <0.06). Myocardial adenosine triphosphate (ATP) levels were assayed after 90 min. ATP levels were 31% higher in both ischemic and non-ischemic myocardium in IMH-treated dogs than in BLH- treated. It was concluded that IMH and BLH are functionally different, and IMH was significantly more effective.

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Oxidative stress enhances phosphorylation of p53 in neonatal rat cardiomyocytes

Molecular and Cellular Biochemistry ◽

10.1007/s11010-007-9470-1 ◽

2007 ◽

Vol 303 (1-2) ◽

pp. 167-174 ◽

Cited By ~ 20

Author(s):

Xilin Long ◽

Michael J. Goldenthal ◽

José Marín-García

Keyword(s):

Oxidative Stress ◽

Neonatal Rat ◽

Rat Cardiomyocytes ◽

Neonatal Rat Cardiomyocytes

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Responses of hypertrophied myocytes to reactive species: implications for glycolysis and electrophile metabolism

Biochemical Journal ◽

10.1042/bj20101390 ◽

2011 ◽

Vol 435 (2) ◽

pp. 519-528 ◽

Cited By ~ 20

Author(s):

Brian E. Sansbury ◽

Daniel W. Riggs ◽

Robert E. Brainard ◽

Joshua K. Salabei ◽

Steven P. Jones ◽

...

Keyword(s):

Oxidative Stress ◽

Oxygen Consumption ◽

Energy Demand ◽

Lactate Production ◽

Fold Increase ◽

Cellular Protein ◽

Reactive Species ◽

Neonatal Rat ◽

Glycolytic Flux ◽

Rat Cardiomyocytes

During cardiac remodelling, the heart generates higher levels of reactive species; yet an intermediate ‘compensatory’ stage of hypertrophy is associated with a greater ability to withstand oxidative stress. The mechanisms underlying this protected myocardial phenotype are poorly understood. We examined how a cellular model of hypertrophy deals with electrophilic insults, such as would occur upon ischaemia or in the failing heart. For this, we measured energetics in control and PE (phenylephrine)-treated NRCMs (neonatal rat cardiomyocytes) under basal conditions and when stressed with HNE (4-hydroxynonenal). PE treatment caused hypertrophy as indicated by augmented atrial natriuretic peptide and increased cellular protein content. Hypertrophied myocytes demonstrated a 2.5-fold increase in ATP-linked oxygen consumption and a robust augmentation of oligomycin-stimulated glycolytic flux and lactate production. Hypertrophied myocytes displayed a protected phenotype that was resistant to HNE-induced cell death and a unique bioenergetic response characterized by a delayed and abrogated rate of oxygen consumption and a 2-fold increase in glycolysis upon HNE exposure. This augmentation of glycolytic flux was not due to increased glucose uptake, suggesting that electrophile stress results in utilization of intracellular glycogen stores to support the increased energy demand. Hypertrophied myocytes also had an increased propensity to oxidize HNE to 4-hydroxynonenoic acid and sustained less protein damage due to acute HNE insults. Inhibition of aldehyde dehydrogenase resulted in bioenergetic collapse when myocytes were challenged with HNE. The integration of electrophile metabolism with glycolytic and mitochondrial energy production appears to be important for maintaining myocyte homoeostasis under conditions of increased oxidative stress.

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Abstract 1582: Adenosine A3 Receptor Deficiency Exerts Unanticipated Protective Effects on Pressure Overloaded-Induced Left Ventricular Hypertrophy and Dysfunction in Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_351 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Zhongbing Lu ◽

John Fassett ◽

Xin Xu ◽

Xinli Hu ◽

Guangshuo Zhu ◽

...

Keyword(s):

Oxidative Stress ◽

Ventricular Hypertrophy ◽

Pressure Overload ◽

Heart Association ◽

Left Ventricular ◽

Neonatal Rat ◽

Protective Effects ◽

Rat Cardiomyocytes ◽

Extracellular Adenosine ◽

Myocardial Oxidative Stress

Endogenous adenosine can protect the overloaded heart against the development of hypertrophy and heart failure, but the contribution of A 1 receptors (A 1 R) and A 3 receptors(A 3 R) is not known. To test the hypothesis A 1 R and A 3 R can protect the heart against systolic overload, we exposed A 3 R gene deficient (A 3 R KO) mice and A 1 R KO mice to transverse aortic constriction (TAC). Contrary to our hypothesis, A 3 R KO attenuated 5 weeks TAC-induced left ventricular (LV) hypertrophy (ratio of ventricular mass/body weight increased to 7.6 ±0.3 mg/g in wild type (Wt) mice as compared with 6.3±0.4 mg/g in KO), fibrosis and dysfunction (LV ejection fraction decreased to 43±2.5% and 55±4.2% in Wt and KO mice, respectively). A 3 R KO also attenuated the TAC-induced increases of myocardial ANP and the oxidative stress markers 3-nitrotyrosine(3-NT ) and 4-hydroxynonenal. In addition, A 3 R KO significantly attenuated TAC-induced activation of multiple MAP kinase pathways, and the activation of Akt-GSK signaling pathway. In contrast, A 1 R-KO increased TAC-induced mortality, but did not alter ventricular hypertrophy or dysfunction compared to Wt mice. In mice in which extracellular adenosine production was impaired by CD73 KO, TAC caused greater hypertrophy and dysfunction, and increased myocardial 3-NT, indicates that extracellular adenosine protects heart against TAC-induced ventricular oxidative stress and hypertrophy. In neonatal rat cardiomyocytes induced to hypertrophy with phenylephrine, the adenosine analogue 2-chloroadenosine (CADO) reduced cell area, protein synthesis, ANP and 3-NT. Antagonism of A3R significantly potentiated the anti-hypertrophic effects of CADO. Our data demonstrated that extracellular adenosine exerts protective effects on the overloaded heart, but A 3 R act counter to the protective effect of adenosine. The data suggest that selective attenuation of A 3 R activity might be a novel approach to attenuate pressure overload-induced myocardial oxidative stress, LV hypertrophy and dysfunction. This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).

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