1. Withaferin A Prevents Myocardial Ischemia/Reperfusion Injury by Upregulating AMP-Activated Protein Kinase-Dependent B-Cell Lymphoma2 Signaling.
- Author
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Guo R, Gan L, Lau WB, Yan Z, Xie D, Gao E, Christopher TA, Lopez BL, Ma X, and Wang Y
- Subjects
- AMP-Activated Protein Kinases genetics, Animals, Cells, Cultured, Disease Models, Animal, Enzyme Activation, Male, Mice, Transgenic, Myocardial Infarction enzymology, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Myocardial Reperfusion Injury enzymology, Myocardial Reperfusion Injury pathology, Myocardial Reperfusion Injury physiopathology, Myocytes, Cardiac enzymology, Myocytes, Cardiac pathology, Phosphorylation, Rats, Sprague-Dawley, Signal Transduction, Ventricular Function, Left drug effects, bcl-2-Associated X Protein metabolism, AMP-Activated Protein Kinases metabolism, Apoptosis drug effects, Myocardial Infarction prevention & control, Myocardial Reperfusion Injury prevention & control, Myocytes, Cardiac drug effects, Proto-Oncogene Proteins c-bcl-2 metabolism, Withanolides pharmacology
- Abstract
Background: Withaferin A (WFA), an anticancer constituent of the plant Withania somnifera, inhibits tumor growth in association with apoptosis induction. However, the potential role of WFA in the cardiovascular system is little-studied and controversial.Methods and Results:Two different doses of WFA were tested to determine their cardioprotective effects in myocardial ischemia/reperfusion (MI/R) injury through evaluation of cardiofunction in wild-type and AMP-activated protein kinase domain negative (AMPK-DN) gentransgenic mice. Surprisingly, cardioprotective effects (improved cardiac function and reduced infarct size) were observed with low-dose WFA (1 mg/kg) delivery but not high-dose (5 mg/kg). Mechanistically, low-dose WFA attenuated myocardial apoptosis. It decreased MI/R-induced activation of caspase 9, the indicator of the intrinsic mitochondrial pathway, but not caspase 8. It also upregulated the level of AMP-activated protein kinase (AMPK) phosphorylation and increased the MI/R inhibited ratio of Bcl2/Bax. In AMPK-deficient mice, WFA did not ameliorate MI/R-induced cardiac dysfunction, attenuate infarct size, or restore the Bcl2/Bax (B-cell lymphoma2/Mcl-2-like protein 4) ratio., Conclusions: These results demonstrated for the first time that low-dose WFA is cardioprotective via upregulation of the anti-apoptotic mitochondrial pathway in an AMPK-dependent manner.
- Published
- 2019
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