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In vitro Assessment of Myocardial Protection following Hypothermia-Preconditioning in a Human Cardiac Myocytes Model
Published on: October 27, 2020
Sirtuin1 mitigates hypoxia-induced cardiomyocyte apoptosis in myocardial infarction via PHD3/HIF-1α
Yafen Chen1,2, Shuyao Shan3, Qiqi Xue1
1Department of Geriatrics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Rui Jin Road II, Shanghai, 200025, People's Republic of China.
Insights
Sirtuin 1 (Sirt1) protects the heart after myocardial infarction by reducing cell death and improving function. It acts via the Phd3/Hif-1α pathway, offering a potential therapeutic target for heart attack recovery.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cellular Stress Response
Background:
- Acute myocardial infarction (AMI) is a major cause of death, leading to heart muscle cell death and dysfunction.
- Sirtuin 1 (Sirt1) is recognized for its role in cell survival and apoptosis, especially during low oxygen conditions.
Purpose of the Study:
- To investigate the role of Sirtuin 1 (Sirt1) in the context of acute myocardial infarction (AMI).
- To elucidate the molecular mechanisms by which Sirt1 influences cardiomyocyte apoptosis and cardiac function post-AMI.
- To explore the Sirt1, Phd3, and Hif-1α signaling pathway in myocardial infarction.
Main Methods:
- Established an AMI mouse model using left anterior descending (LAD) artery ligation.
- Analyzed gene expression changes in the infarcted heart tissue and in primary cardiomyocytes under hypoxia.
- Utilized lentivirus to overexpress Sirt1 in the peri-infarct region and performed functional assessments and apoptosis assays.
Main Results:
- AMI induced a time-dependent decrease in Sirt1 and Phd3, with increased Hif-1α and cleaved caspase-3.
- Sirt1 overexpression in cardiomyocytes counteracted hypoxia-induced apoptosis by upregulating Phd3 and downregulating Hif-1α and cleaved caspase-3.
- In vivo, Sirt1 administration reduced infarct size, decreased cardiomyocyte apoptosis, and improved cardiac function.
Conclusions:
- Sirtuin 1 (Sirt1) demonstrates significant cardioprotective effects following myocardial infarction (MI).
- Sirt1 mitigates cardiomyocyte apoptosis and reduces infarct size, thereby improving cardiac function post-MI.
- The protective mechanism of Sirt1 is primarily mediated through the Phd3/Hif-1α signaling pathway.
Background:
Acute myocardial infarction (AMI) is a leading cause of mortality, characterized by myocardial ischemia that induces cardiomyocyte apoptosis and subsequent cardiac dysfunction. Sirtuin 1 (Sirt1) has emerged as a key regulator of cell survival and apoptosis, particularly under hypoxic conditions.
Methods:
An AMI animal model was established via ligation of the left anterior descending (LAD) coronary artery. Gene expression in the infarcted region was evaluated at various time points. Sirt1 overexpression and control lentivirus were administered to the peri-infarct region of mice heart. After LAD ligation, assessment on myocardial infarct size, cardiac function, and cardiomyocyte apoptosis were performed. In vitro, primary mouse cardiomyocytes subjected to hypoxia were analyzed for gene expression, while interactions among Sirt1, Phd3, and Hif-1α were explored using diverse treatment approaches.
Results:
A significant reduction in Sirt1 and Phd3 expression, along with an increase in Hif-1α and cleaved caspase-3, was observed in a time-dependent manner post-myocardial infarction (MI). In vitro findings revealed that hypoxia decreased nuclear Sirt1 and cytoplasmic Phd3 levels while promoting a time-dependent increase in Hif-1α and cleaved caspase-3. Furthermore, Sirt1 overexpression enhanced Phd3 expression in cardiomyocytes, suppressed Hif-1α and cleaved caspase-3 levels, and alleviated hypoxia-induced cardiomyocyte apoptosis. Notably, knockdown of Phd3 negated Sirt1's inhibitory effect on Hif-1α, whereas Hif-1α knockdown promoted Sirt1 expression. Sirt1 overexpression reduced infarct size, decreased cardiomyocyte apoptosis, and improved cardiac function.
Conclusions:
Sirt1 effectively reduces cardiomyocyte apoptosis and myocardial infarction size while enhancing cardiac function post-MI, primarily through the Phd3/Hif-1α signaling pathway.
