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.