Higenamine protects ischemia/reperfusion induced cardiac injury and myocyte apoptosis through activation of β2-AR/PI3K/AKT signaling pathway.
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.
['Wu|Mei-ping|MP|', 'Zhang|Yi-shuai|YS|', 'Zhou|Qian-mei|QM|', 'Xiong|Jian|J|', 'Dong|Yao-rong|YR|', 'Yan|Chen|C|']
D000470:Alkaloids D000818:Animals D017209:Apoptosis D002316:Cardiotonic Agents D053148:Caspase 3 D002478:Cells, Cultured D006861:Hydrogen Peroxide D008297:Male D008810:Mice, Inbred C57BL D015428:Myocardial Reperfusion Injury D009206:Myocardium D032383:Myocytes, Cardiac D019869:Phosphatidylinositol 3-Kinases D051057:Proto-Oncogene Proteins c-akt D017207:Rats, Sprague-Dawley D018343:Receptors, Adrenergic, beta-2 D015398:Signal Transduction D044005:Tetrahydroisoquinolines
Higenamine Ischemia/reperfusion Apoptosis Cardiomyocyte Beta2-adrenergic receptor Higenamine (PubChem CID: 440927)