Higenamine protects ischemia/reperfusion induced cardiac injury and myocyte apoptosis through activation of β2-AR/PI3K/AKT signaling pathway.
Higenamine protects ischemia/reperfusion induced cardiac injury and myocyte apoptosis through activation of β2-AR/PI3K/AKT signaling pathway.
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Higenamine 通过激活 β2-AR/PI3K/AKT 信号通路保护缺血/再灌注引起的心脏损伤和心肌细胞凋亡
DOI：
10.1016/j.phrs.2015.12.032
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发表时间：
2016-02
影响因子：
9.3
通讯作者：
Yan C
中科院分区：
文献类型：
--
作者：
Wu MP;Zhang YS;Zhou QM;Xiong J;Dong YR;Yan C
心肌细胞凋亡参与缺血性心脏损伤和心力衰竭的发生发展。去甲乌药碱是中国草药乌头根的关键成分，在东方亚洲国家数千年来一直被用于治疗心力衰竭的症状。已显示去甲乌药碱在包括心肌细胞在内的少数细胞类型中具有抗凋亡作用。然而，去甲乌药碱在心脏中的药理作用靶点和分子机制仍没有完全阐明。本文报道去甲乌药碱通过选择性激活β 2-肾上腺素能受体（β2-AR）保护心肌细胞凋亡和缺血/再灌注损伤。特别是，我们表明去甲组胺显着减少了小鼠I/R诱导的心肌梗死。在这两个主要的新生大鼠和成年小鼠心室肌细胞，我们表明去甲乌药碱抑制细胞凋亡，也减少了细胞凋亡的生化标志物，如裂解半胱天冬酶3和9。更重要的是，我们发现去甲乌药碱在心肌细胞中的抗凋亡作用被β2-AR拮抗剂完全消除，而不是β1-AR拮抗剂。此外，我们证实去甲乌药碱以β2-AR依赖的方式减轻了I/R诱导的小鼠心肌损伤，并减少了切割的半胱氨酸天冬氨酸蛋白酶。去甲乌药碱刺激AKT磷酸化，并需要PI 3 K激活心肌细胞中的抗凋亡作用。这些结果共同表明去甲乌药碱的抗凋亡和心脏保护作用是由β2-AR/PI 3 K/AKT级联介导的。
Cardiomyocyte apoptosis contributes to ischemic cardiac injury and the development of heart failure. Higenamine is a key component of the Chinese herb aconite root that has been prescribed for treating symptoms of heart failure for thousands of years in the oriental Asian countries. It has been shown that higenamine has anti-apoptotic effects in a few cell types including cardiomyocytes. However, the pharmacological target and molecular mechanism of higenamine in the heart are still not fully illustrated. Herein, we report that higenamine protected myocyte apoptosis and ischemia/reperfusion (I/R) injury through selective activation of beta2-adrenergic receptor (β2-AR). In particular, we show that higenamine significantly reduced I/R-induced myocardial infarction in mice. In both primary neonatal rat and adult mouse ventricular myocytes, we show higenamine inhibited cell apoptosis and also reduced biochemical markers of apoptosis such as cleaved caspase 3 and 9. More importantly, we show that the anti-apoptotic effects of higenamine in cardiomyocytes were completely abolished by β2-AR but not β1-AR antagonism. Furthermore, we confirmed that higenamine attenuated I/R-induced myocardial injury and reduced cleaved caspases in a β2-AR dependent manner in intact mouse hearts. Higenamine stimulated AKT phosphorylation and required PI3K activation for the anti-apoptotic effect in cardiomyocytes. These findings together suggest that anti-apoptotic and cardiac protective effects of higenamine are mediated by the β2-AR/PI3K/AKT cascade.