Withaferin A Prevents Myocardial Ischemia/Reperfusion Injury by Upregulating AMP-Activated Protein Kinase-Dependent B-Cell Lymphoma2 Signaling

• Published in: Circulation Journal Vol. 83; no. 8; pp. 1726 - 1736
• Main Authors: Guo, Rui, Gan, Lu, Lau, Wayne Bond, Yan, Zheyi, Xie, Dina, Gao, Erhe, Christopher, Theodore A, Lopez, Bernard L., Ma, Xinliang, Wang, Yajing
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Circulation Society 25.07.2019
• Subjects: AMP-activated protein kinase; Apoptosis; Bcl-2/Bax; Cardiac function; Withaferin A; Bcl-2/Bax; Withaferin A; AMP-activated protein kinase; Cardiac function; Apoptosis
• ISSN: 1346-9843; 1347-4820
• DOI: 10.1253/circj.CJ-18-1391

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.