Withaferin A Prevents Myocardial Ischemia/Reperfusion Injury by Upregulating AMP-Activated Protein Kinase-Dependent B-Cell Lymphoma2 Signaling
Withaferin A Prevents Myocardial Ischemia/Reperfusion Injury by Upregulating AMP-Activated Protein Kinase-Dependent B-Cell Lymphoma2 Signaling
复制标题
醉茄素 A 通过上调 AMP 激活蛋白激酶依赖性 B 细胞淋巴瘤信号传导来预防心肌缺血/再灌注损伤
DOI：
10.1253/circj.cj-18-1391
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发表时间：
2019-08-01
影响因子：
3.3
通讯作者：
Wang, Yajing
中科院分区：
文献类型：
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作者：
Guo, Rui;Gan, Lu;Wang, Yajing
背景：睡茄素 A (WFA) 是睡茄植物的一种抗癌成分，可抑制与细胞凋亡诱导相关的肿瘤生长。然而，WFA 在心血管系统中的潜在作用研究很少，且存在争议。 方法和结果：通过评估野生型和 AMP 激活蛋白激酶结构域阴性 (AMPK-DN) 基因转基因小鼠的心功能，测试了两种不同剂量的 WFA，以确定其对心肌缺血/再灌注 (MI/R) 损伤的心脏保护作用。令人惊讶的是，低剂量 WFA (1 mg/kg) 递送观察到心脏保护作用（改善心脏功能和减少梗塞面积），但高剂量 (5 mg/kg) 则没有观察到。从机制上讲，低剂量 WFA 可减弱心肌细胞凋亡。它降低了 MI/R 诱导的 caspase 9（线粒体内在途径的指标）的激活，但不降低 caspase 8。它还上调 AMP 激活蛋白激酶 (AMPK) 磷酸化水平，并增加 MI/R 抑制 Bcl2/Bax 的比率。在 AMPK 缺陷小鼠中，WFA 并未改善 MI/R 诱导的心脏功能障碍、减轻梗死面积或恢复 Bcl2/Bax（B 细胞淋巴瘤 2/Mcl-2 样蛋白 4）比率。 结论：这些结果首次证明，低剂量 WFA 通过以 AMPK 依赖性方式上调抗凋亡线粒体途径来发挥心脏保护作用。
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 antiapoptotic mitochondrial pathway in an AMPK-dependent manner.