Metformin attenuates ischemia/reperfusion-induced apoptosis of cardiac cells by downregulation of p53/microRNA-34a via activation SIRT1

2021 ◽  
Author(s):  
Weiwei Li ◽  
Sheng Jin ◽  
Jie Hao ◽  
Yun Shi ◽  
Wenjie Li ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Coronary Intervention ◽  
Cardiac Cells ◽  
H9c2 Cells ◽  
St Segment Elevation ◽  
St Segment ◽  
Associated Proteins ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis

Metformin has been demonstrated to be beneficial for the treatment of an impaired myocardium as a result of ischemia reperfusion (I/R) injury and miR-34a may be involved in this process. The aim of the present study was to determine the mechanisms by which metformin attenuated myocardial I/R injury induced apoptosis. In the in vivo I/R rat model, metformin reduced the area of damaged myocardium and CKMB activity for protection of the myocardium. Metformin also reduced apoptosis, the expression of apoptosis associated proteins and miR-34a, which resulted in corresponding changes of Bcl-2 expression. To further examine the role of miR-34a, H9C2 cells were transfected by miR-34a mimic and inhibitor. Overexpression of miR-34a increased apoptosis in H9C2 cells induced by OGD/R and knockdown of miR-34a reduced apoptosis. Metformin decreased the deacetylation activity of SIRT 1 resulting in reduced Ac-p53 levels, which reduced the levels of pri-miR-34a. To confirm these results clinically, 90 patients with ST-segment elevation myocardial infarction following percutaneous coronary intervention were recruited. Patients who took metformin regularly before infarction had lower miR-34a levels and lower serum CKMB activity. Metformin also improved sum ST-segment recovery following I/R injury. In conclusion, metformin may be helpful in the treatment of myocardial ischemia reperfusion.

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.

scholarly journals LncRNA PVT1 Knockdown Ameliorates Myocardial Ischemia Reperfusion Damage via Suppressing Gasdermin D-Mediated Pyroptosis in Cardiomyocytes

2021 ◽  
Vol 8 ◽  
Author(s):  
Cuizhi Li ◽  
Huafeng Song ◽  
Chunlin Chen ◽  
Shaoxian Chen ◽  
Qiyu Zhang ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Cell Viability ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
H9c2 Cells ◽  
Myocardial Ischemia Reperfusion ◽  
Tissue Specimens ◽  
Masson Staining

Objective: Myocardial ischemia reperfusion (I/R) damage is a life-threatening vascular emergency after myocardial infarction. Here, we observed the cardioprotective effect of long non-coding RNA (lncRNA) PVT1 knockdown against myocardial I/R damage.Methods: This study constructed a myocardial I/R-induced mouse model and a hypoxia/reoxygenation (H/R)-treated H9C2 cells. PVT1 expression was examined via RT-qPCR. After silencing PVT1 via shRNA against PVT1, H&E, and Masson staining was performed to observe myocardial I/R damage. Indicators of myocardial injury including cTnI, LDH, BNP, and CK-MB were examined by ELISA. Inflammatory factors (TNF-α, IL-1β, and IL-6), Gasdermin D (GSDMD), and Caspase1 were detected via RT-qPCR, western blot, immunohistochemistry, or immunofluorescence. Furthermore, CCK-8 and flow cytometry were presented for detecting cell viability and apoptosis.Results: LncRNA PVT1 was markedly up-regulated in myocardial I/R tissue specimens as well as H/R-induced H9C2 cells. Silencing PVT1 significantly lowered serum levels of cTnI, LDH, BNP, and CK-MB in myocardial I/R mice. H&E and Masson staining showed that silencing PVT1 alleviated myocardial I/R injury. PVT1 knockdown significantly lowered the production and release of inflammatory factors as well as inhibited the expression of GSDMD-N and Caspase1 in myocardial I/R tissue specimens as well as H/R-induced H9C2 cells. Moreover, silencing PVT1 facilitated cell viability and induced apoptosis of H/R-treated H9C2 cells.Conclusion: Our findings demonstrated that silencing PVT1 could alleviate myocardial I/R damage through suppressing GSDMD-mediated pyroptosis in vivo and in vitro. Thus, PVT1 knockdown may offer an alternative therapeutic strategy against myocardial I/R damage.

scholarly journals Mangiferin Attenuates Myocardial Ischemia-Reperfusion Injury via MAPK/Nrf-2/HO-1/NF-κB In Vitro and In Vivo

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Kun Liu ◽  
Fei Wang ◽  
Shuo Wang ◽  
Wei-Nan Li ◽  
Qing Ye
Keyword(s):  
Oxidative Stress ◽  
Coronary Artery ◽  
Myocardial Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
H9c2 Cells ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

The aim of this study was to investigate the cardioprotective effect of mangiferin (MAF) in vitro and in vivo. Oxidative stress and inflammatory injury were detected in coronary artery ligation in rats and also in hypoxia-reoxygenation- (H/R-) induced H9c2 cells. MAF inhibited myocardial oxidative stress and proinflammatory cytokines in rats with coronary artery occlusion. The ST segment of MAF treatment groups also resumed. Triphenyltetrazolium chloride (TTC) staining and pathological analysis showed that MAF could significantly reduce myocardial injury. In vitro data showed that MAF could improve hypoxia/reoxygenation- (H/R-) induced H9c2 cell activity. In addition, MAF could significantly reduce oxidative stress and inflammatory pathway protein expression in H/R-induced H9c2 cells. This study has clarified the protective effects of MAF on myocardial injury and also confirmed that oxidative stress and inflammation were involved in the myocardial ischemia-reperfusion injury (I/R) model.

Abstract 221: miR-19b Protects Myocardial Ischemia Reperfusion Injury

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Dongchao Lv ◽  
Shengguang Ding ◽  
Ping Chen ◽  
Yihua Bei ◽  
Chongjun Zhong ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Cellular Proliferation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
H9c2 Cells ◽  
Protein Levels ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis

Ischemia-reperfusion injury (IRI) following acute myocardial infarction (AMI) has no effective treatment and a poor prognosis. microRNA (miRNA)-19b is a key functional member of miRNA-19-72 cluster family, regulating cellular proliferation, apoptosis, differentiation, and metabolism. Dysregulation of the miR-19b cluster is critically involved in a spectrum of cardiovascular diseases. However, the role of miR-19b in myocardial IRI is unknown. In this study, we found that miR-19b was downregulated in a mouse model of IRI. Meanwhile, about 50% downregulation of miR-19b was detected in H2O2-treated H9C2 cells mimicking myocardial IRI. We also found that overexpression of miR-19b decreased H2O2-induced apoptosis (36.02%±3.92% vs 29.34%±0.79% in nc-mimics vs miR-19b-mimics, respectively) and necrosis (23.11%±1.64% vs 18.76%±0.71% in nc-mimics vs miR-19b-mimics, respectively), and increased proliferation of H9C2 cells in vitro, while downregulation of miR-19b had reverse effects. Furthermore, PTEN, a previously validated target gene of miR-19b, has been found to be negatively regulated by miR-19b at protein levels in H9C2 cells. These data reveal the potential of miR-19b as a therapeutic target for myocardial IRI.

scholarly journals Lingonberry anthocyanins protect cardiac cells from oxidative-stress-induced apoptosis

2017 ◽  
Vol 95 (8) ◽  
pp. 904-910 ◽  
Author(s):  
Cara K. Isaak ◽  
Jay C. Petkau ◽  
Heather Blewett ◽  
Karmin O ◽  
Yaw L. Siow
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Cells ◽  
Control Group ◽  
Protective Effects ◽  
H9c2 Cells ◽  
Induced Apoptosis ◽  
Hoechst Staining

Lingonberry grown in northern Manitoba, Canada, contains exceptionally high levels of anthocyanins and other polyphenols. Previous studies from our lab have shown that lingonberry anthocyanins can protect H9c2 cells from ischemia–reperfusion injury and anthocyanin-rich diets have been shown to be associated with decreased cardiovascular disease and mortality. Oxidative stress can impair function and trigger apoptosis in cardiomyocytes. This study investigated the protective effects of physiologically relevant doses of lingonberry extracts and pure anthocyanins against hydrogen-peroxide-induced cell death. Apoptosis and necrosis were detected in H9c2 cells after hydrogen peroxide treatment via flow cytometry using FLICA 660 caspase 3/7 combined with YO-PRO-1 and then confirmed with Hoechst staining and fluorescence microscopy. Each of the 3 major anthocyanins found in lingonberry (cyanidin-3-galactoside, cyanidin-3-glucoside, and cyanidin-3-arabinoside) was protective against hydrogen-peroxide-induced apoptosis in H9c2 cells at 10 ng·mL−1 (20 nmol·L−1) and restored the number of viable cells to match the control group. A combination of the 3 anthocyanins was also protective and a lingonberry extract tested at 3 concentrations produced a dose-dependent protective effect. Lingonberry anthocyanins protected cardiac cells from oxidative-stress-induced apoptosis and may have cardioprotective effects as a dietary modification.

scholarly journals (Pro)renin Receptor Contributes to Hypoxia/Reoxygenation-Induced Apoptosis and Autophagy in Myocardial Cells via the β-Catenin Signaling Pathway

2020 ◽  
pp. 427-438
Author(s):  
X GAO ◽  
S ZHANG ◽  
D WANG ◽  
Y CHENG ◽  
Y JIANG ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cell Counting ◽  
H9c2 Cells ◽  
Related Factors ◽  
Myocardial Ischemia Reperfusion ◽  
Induced Apoptosis ◽  
Hypoxia Reoxygenation

(Pro)renin receptor (PRR) contributes to regulating many physiological and pathological processes; however, the role of PRR-mediated signaling pathways in myocardial ischemia/reperfusion injury (IRI) remains unclear. In this study, we used an in vitro model of hypoxia/reoxygenation (H/R) to mimic IRI and carried out PRR knockdown by siRNA and PRR overexpression using cDNA in H9c2 cells. Cell proliferation activity was examined by MTT and Cell Counting Kit-8 (CCK-8) assays. Apoptosis-related factors, autophagy markers and β-catenin pathway activity were assessed by real-time PCR and western blotting. After 24 h of hypoxia followed by 2 h of reoxygenation, the expression levels of PRR, LC3B-I/II, Beclin1, cleaved caspase-3, cleaved caspase-9 and Bax were upregulated, suggesting that apoptosis and autophagy were increased in H9c2 cells. Contrary to the effects of PRR downregulation, the overexpression of PRR inhibited proliferation, induced apoptosis, increased the expression of pro-apoptotic factors and autophagy markers, and promoted activation of the β-catenin pathway. Furthermore, all these effects were reversed by treatment with the β-catenin antagonist DKK-1. Thus, we concluded that PRR activation can trigger H/R-induced apoptosis and autophagy in H9c2 cells through the β-catenin signaling pathway, which may provide new therapeutic targets for the prevention and treatment of myocardial IRI.

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