scholarly journals Bnip3 functions as a mitochondrial sensor of oxidative stress during myocardial ischemia and reperfusion

2008 ◽  
Vol 295 (5) ◽  
pp. H2025-H2031 ◽  
Author(s):  
Dieter A. Kubli ◽  
Melissa N. Quinsay ◽  
Chengqun Huang ◽  
Youngil Lee ◽  
Åsa B. Gustafsson
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Myocardial Ischemia ◽  
Disulfide Bonds ◽  
Transmembrane Domain ◽  
Ischemia Reperfusion ◽  
Cysteine Residue ◽  
Interacting Protein ◽  
Myocardial Ischemia And Reperfusion ◽  
Domain 3

Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (Bnip3) is a member of the Bcl-2 homology domain 3-only subfamily of proapoptotic Bcl-2 proteins and is associated with cell death in the myocardium. In this study, we investigated the potential mechanism(s) by which Bnip3 activity is regulated. We found that Bnip3 forms a DTT-sensitive homodimer that increased after myocardial ischemia-reperfusion (I/R). The presence of the antioxidant N-acetylcysteine reduced I/R-induced homodimerization of Bnip3. Overexpression of Bnip3 in cells revealed that most of exogenous Bnip3 exists as a DTT-sensitive homodimer that correlated with increased cell death. In contrast, endogenous Bnip3 existed mainly as a monomer under normal conditions in the heart. Screening of the Bnip3 protein sequence revealed a single conserved cysteine residue at position 64. Mutation of this cysteine to alanine (Bnip3C64A) or deletion of the NH2-terminus (amino acids 1-64) resulted in reduced cell death activity of Bnip3. Moreover, mutation of a histidine residue in the COOH-terminal transmembrane domain to alanine (Bnip3H173A) almost completely inhibited the cell death activity of Bnip3. Bnip3C64A had a reduced ability to interact with Bnip3, whereas Bnip3H173A was completely unable to interact with Bnip3, suggesting that homodimerization is important for Bnip3 function. A consequence of I/R is the production of reactive oxygen species and oxidation of proteins, which promotes the formation of disulfide bonds between proteins. Thus, these experiments suggest that Bnip3 functions as a redox sensor where increased oxidative stress induces homodimerization and activation of Bnip3 via cooperation of the NH2-terminal cysteine residue and the COOH-terminal transmembrane domain.

scholarly journals The Role of Oxidative Stress in Myocardial Ischemia and Reperfusion Injury and Remodeling: Revisited

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Gino A. Kurian ◽  
Rashmi Rajagopal ◽  
Srinivasan Vedantham ◽  
Mohanraj Rajesh
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Antioxidant Defenses ◽  
Common Denominator ◽  
Myocardial Ischemia And Reperfusion ◽  
Reductive Stress ◽  
Myocardial Infraction

Oxidative and reductive stress are dual dynamic phases experienced by the cells undergoing adaptation towards endogenous or exogenous noxious stimulus. The former arises due to the imbalance between the reactive oxygen species production and antioxidant defenses, while the latter is due to the aberrant increase in the reducing equivalents. Mitochondrial malfunction is the common denominator arising from the aberrant functioning of the rheostat that maintains the homeostasis between oxidative and reductive stress. Recent experimental evidences suggest that the maladaptation during oxidative stress could play a pivotal role in the pathophysiology of major cardiovascular diseases such as myocardial infraction, atherosclerosis, and diabetic cardiovascular complications. In this review we have discussed the role of oxidative and reductive stress pathways in the pathogenesis of myocardial ischemia/reperfusion injury and diabetic cardiomyopathy (DCM). Furthermore, we have provided impetus for the development of subcellular organelle targeted antioxidant drug therapy for thwarting the deterioration of the failing myocardium in the aforementioned cardiovascular conditions.

scholarly journals Salvia miltiorrhiza treatment during early reperfusion reduced postischemic myocardial injury in the rat

2007 ◽  
Vol 85 (10) ◽  
pp. 1012-1019 ◽  
Author(s):  
Ruqiong Nie ◽  
Rui Xia ◽  
Xingwu Zhong ◽  
Zhengyuan Xia
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Functional Recovery ◽  
Salvia Miltiorrhiza ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Water Soluble ◽  
Causative Role ◽  
Myocardial Ischemia And Reperfusion ◽  
Early Reperfusion

Oxidative stress may play a causative role in myocardial ischemia–reperfusion injury. However, it is a relatively understudied aspect regarding an optimal timing of antioxidant intervention during ischemia–reperfusion. The present study investigates the effect of different treatment regimens of Salvia miltiorrhiza (SM) herb extracts containing phenolic compounds that possess potent antioxidant properties on postischemic myocardial functional recovery in the setting of global myocardial ischemia and reperfusion. Langendorff-perfused rat hearts were subjected to 40 min of global ischemia at 37 °C followed by 60 min of reperfusion, and were randomly assigned into the untreated control and 2 SM-treated groups (n = 7 per group). In treatment 1 (SM1), 3 mg/mL of water soluble extract of SM was given for 10 min before ischemia and continued during ischemia through the aorta at a reduced flow rate of 60 μL/min, but not during reperfusion. In treatment 2 (SM2), SM (3 mg/mL) was given during the first 15 min of reperfusion. During ischemia, hearts in the control and SM2 groups were given physiological saline at 60 μL/min. The SM1 treatment reduced the production of 15-F2t-isoprostane, a specific index of oxidative stress-induced lipid peroxidation, during ischemia (94 ± 20, 43 ± 6, and 95 ± 15 pg/mL in the coronary effluent in control, SM1, and SM2 groups, respectively; p < 0.05, SM1 vs. control or SM2) and postponed the onset of ischemic contracture. However, SM2, but not the SM1 regimen, significantly reduced 15-F2t-isoprostane production during early reperfusion and led to optimal postischemic myocardial functional recovery (left ventricular developed pressure 51 ± 4, 46 ± 4, and 60 ± 6 mmHg in the control, SM1, and SM2 groups, respectively, at 60 min of reperfusion; p < 0.05, SM2 vs. control or SM1) and reduced myocardial infarct size as measured by triphenyltetrazolium chloride staining (26% ± 2%, 22% ± 2%, and 20% ± 2% of the total area in the control, SM1, and SM2 groups, respectively, p < 0.05, SM2 vs. control). It is concluded that S. miltiorrhiza could be beneficial in the treatment of myocardial ischemic injury and the timing of administration seems important.

Abstract 628: Pro-Apoptotic Bnip3 Functions as a Mitochondrial Sensor of Oxidative Stress in Myocardial Ischemia/Reperfusion

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Dieter A Kubli ◽  
Melissa N Quinsay ◽  
Asa B Gustafsson
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Disulfide Bonds ◽  
Ischemia Reperfusion ◽  
Wild Type ◽  
Redox Sensor ◽  
Sds Page ◽  
Ros Scavenger ◽  
Tm Domain ◽  
Myocardial Ischemia Reperfusion

Bnip3 is a member of the BH3-only subfamily of pro-apoptotic Bcl-2 proteins and is associated with mitochondrial dysfunction and cell death in the myocardium. We previously found that Bnip3 contributes to ischemia/reperfusion (I/R) injury, but it is not known how I/R causes activation of Bnip3. We have investigated potential mechanism(s) by which Bnip3 activity is regulated. Western blot analysis of heart lysates revealed that Bnip3 forms a ∼48 kDa complex after I/R that is sensitive to reduction by DTT. Complex formation was reduced when hearts were perfused with the reactive oxygen species (ROS) scavenger N-acetyl cysteine prior to I/R. The complex also increased in isolated myocytes treated with hydrogen peroxide, suggesting that the DTT-sensitive complex is formed by increased oxidative stress. To further investigate the function of this complex, we overexpressed Bnip3 in HL-1 myocytes and found that most of Bnip3 existed in the 48-kDa complex which correlated with increased cell death. In contrast, endogenous Bnip3 in the heart exists mainly as a monomer under normal conditions. Scanning of the Bnip3 protein sequence revealed a single conserved Cys residue at position 64, which may be susceptible to oxidation. Mutation of the Cys to an Ala or deletion of the N-term (aa 1–64) resulted in reduced cell death activity of Bnip3 compared to wild type when overexpressed in HL-1 myocytes. Separation of purified Bnip3 on SDS-PAGE showed the presence of the same DTT sensitive complex, suggesting that the complex is a Bnip3 homodimer. The transmembrane (TM) domain of Bnip3 has previously been identified to be important for homodimerization, and contains a His residue at position 173 that is essential for homodimerization. Mutation of the His to an Ala also resulted in reduced cell death activity of Bnip3 compared to wild type when overexpressed in HL-1 myocytes, suggesting that homodimerization is important for cell death activity of Bnip3. A consequence of I/R is the production of ROS and oxidation of proteins, which promotes formation of Cys disulfide bonds between proteins. Thus, these studies suggest that Bnip3 functions as a redox sensor in cells where increased oxidative stress induces homodimerization of Bnip3 via N-terminal Cys residue and the C-terminal TM domain.

Icaritin Attenuates Myocardial Ischemia and Reperfusion Injury Via Anti-Inflammatory and Anti-Oxidative Stress Effects in Rats

2015 ◽  
Vol 43 (06) ◽  
pp. 1083-1097 ◽  
Author(s):  
Wei Zhang ◽  
Baichun Xing ◽  
Linlin Yang ◽  
Jialun Shi ◽  
Xinmin Zhou
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Inflammatory Cytokine ◽  
Ischemia Reperfusion ◽  
Cardiac Differentiation ◽  
Ischemia And Reperfusion Injury ◽  
Chinese Medicinal Herb ◽  
Myocardial Ischemia And Reperfusion ◽  
Akt Phosphorylation ◽  
Anti Inflammatory

Icaritin (ICT) is a traditional Chinese medicinal herb proved to be neuroprotective and exerts promoting effects on cardiac differentiation. However, its role in cardioprotection against myocardial ischemia/reperfusion (MI/R) injury remains largely unknown. This study aimed to investigate the effects of ICT treatment on MI/R injury and the underlying mechanisms. Rats were subjected to 30 min of myocardial ischemic insult followed by 3 h of reperfusion. ICT (3, 10, and 30 mg/kg) was administered intraperitoneally 10 min before reperfusion. ICT treatment at the dose of 10 and 30 mg/kg improved cardiac function and limited infarct size following MI/R. Meanwhile, ICT reduced plasma creatine kinase (CK), lactate dehydrogenase (LDH) activities and cardiomyocyte apoptosis in I/R heart tissue. Moreover, ICT treatment not only inhibited the pro-inflammatory cytokine TNF-α production and increased the anti-inflammatory cytokine IL-10 level in myocardium but also reduced the increase in the generation of superoxide content and malondialdehyde (MDA) formation and simultaneously increased the anti-oxidant capability in I/R hearts. Furthermore, ICT treatment increased Akt phosphorylation and inhibited PTEN expression in I/R hearts. PI3K inhibitor wortmannin inhibited ICT-enhanced Akt phosphorylation, and blunted ICT-mediated anti-oxidative and anti-inflammatory effects and cardioprotection. Our study indicated for the first time that ICT reduces inflammation and oxidative stress and protects against MI/R injury in rats, which might be via a PI3K–Akt-dependent mechanism.

scholarly journals microRNA-130a-5p suppresses myocardial ischemia reperfusion injury by downregulating the HMGB2/NF-κB axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yong Li ◽  
Hongbo Zhang ◽  
Zhanhu Li ◽  
Xiaoju Yan ◽  
Yuan Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Mouse Models ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Luciferase Reporter ◽  
Gene Assay ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Abstract Background Myocardial ischemia reperfusion injury (MIRI) is defined as tissue injury in the pathological process of progressive aggravation in ischemic myocardium after the occurrence of acute coronary artery occlusion. Research has documented the involvement of microRNAs (miRs) in MIRI. However, there is obscure information about the role of miR-130a-5p in MIRI. Herein, this study aims to investigate the effect of miR-130a-5p on MIRI. Methods MIRI mouse models were established. Then, the cardiac function and hemodynamics were detected using ultrasonography and multiconductive physiological recorder. Functional assays in miR-130a-5p were adopted to test the degrees of oxidative stress, mitochondrial functions, inflammation and apoptosis. Hematoxylin and eosin (HE) staining was performed to validate the myocardial injury in mice. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was employed to assess the expression patterns of miR-130a-5p, high mobility group box (HMGB)2 and NF-κB. Then, dual-luciferase reporter gene assay was performed to elucidate the targeting relation between miR-130a-5p and HMGB2. Results Disrupted structural arrangement in MIRI mouse models was evident from HE staining. RT-qPCR revealed that overexpressed miR-130a-5p alleviated MIRI, MIRI-induced oxidative stress and mitochondrial disorder in the mice. Next, the targeting relation between miR-130a-5p and HMGB2 was ascertained. Overexpressed HMGB2 annulled the protective effects of miR-130a-5p in MIRI mice. Additionally, miR-130a-5p targets HMGB2 to downregulate the nuclear factor kappa-B (NF-κB) axis, mitigating the inflammatory injury induced by MIRI. Conclusion Our study demonstrated that miR-130a-5p suppresses MIRI by down-regulating the HMGB2/NF-κB axis. This investigation may provide novel insights for development of MIRI treatments.

scholarly journals ELAVL1 is transcriptionally activated by FOXC1 and promotes ferroptosis in myocardial ischemia/reperfusion injury by regulating autophagy

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Hui-Yong Chen ◽  
Ze-Zhou Xiao ◽  
Xiao Ling ◽  
Rong-Ning Xu ◽  
Peng Zhu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Beclin 1 ◽  
Myocardial Cells ◽  
Myocardial Ischemia And Reperfusion ◽  
Functional Roles ◽  
Cellular Iron ◽  
Luciferase Activity Assay ◽  
Myocardial Ischemia Reperfusion

Abstract Aims Myocardial ischemia is the most common form of cardiovascular disease and the leading cause of morbidity and mortality. Understanding the mechanisms is very crucial for the development of effective therapy. Therefore, this study aimed to investigate the functional roles and mechanisms by which ELAVL1 regulates myocardial ischemia and reperfusion (I/R) injury. Methods Mouse myocardial I/R model and cultured myocardial cells exposed to hypoxia/reperfusion (H/R) were used in this study. Features of ferroptosis were evidenced by LDH activity, GPx4 activity, cellular iron, ROS, LPO, and GSH levels. The expression levels of autophagy markers (Beclin-1, p62, LC3), ELAVL1 and FOXC1 were measured by qRT-PCR, immunostaining and western blot. RIP assay, biotin-pull down, ChIP and dual luciferase activity assay were employed to examine the interactions of ELAVL1/Beclin-1 mRNA and FOXC1/ELAVL1 promoter. CCK-8 assay was used to examine viability of cells. TTC staining was performed to assess the myocardial I/R injury. Results Myocardial I/R surgery induced ferroptosis and up-regulated ELAVL1 level. Knockdown of ELAVL1 decreased ferroptosis and ameliorated I/R injury. Si-ELAVL1 repressed autophagy and inhibition of autophagy by inhibitor suppressed ferroptosis and I/R injury in myocardial cells. Increase of autophagy could reverse the effects of ELAVL1 knockdown on ferroptosis and I/R injury. ELAVL1 directly bound with and stabilized Beclin-1 mRNA. Furthermore, FOXC1 bound to ELAVL1 promoter region and activated its transcription upon H/R exposure. Conclusion FOXC1 transcriptionally activated ELAVL1 may promote ferroptosis during myocardial I/R by modulating autophagy, leading to myocardial injury. Inhibition of ELAVL1-mediated autophagic ferroptosis would be a new viewpoint in the treatment of myocardial I/R injury.

scholarly journals iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1446
Author(s):  
Tingting Jin ◽  
Jun Lin ◽  
Yingchao Gong ◽  
Xukun Bi ◽  
Shasha Hu ◽  
...  
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Myocardial Ischemia ◽  
Ischemic Heart Disease ◽  
Er Stress ◽  
Ischemia Reperfusion ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis

Both calcium-independent phospholipase A2 beta (iPLA2β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2β knockout mice and siRNA mediated iPLA2β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2β. Our data demonstrate the increase of iPLA2β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2β ameliorates ER stress and decreases cell death. Mechanistically, iPLA2β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.

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