Higenamine protects ischemia/reperfusion induced cardiac injury and myocyte apoptosis through activation of β₂-AR/PI3K/AKT signaling pathway

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• 作者：Mei-ping Wu^a ; ^b ; ^{meipingwu1207@hotmail.com" class="auth_mail" title="E-mail the corresponding author} ; Yi-shuai Zhang^b ; ^{Yishuai_zhang@outlook.com" class="auth_mail" title="E-mail the corresponding author} ; Qian-mei Zhou^c ; ^{tazhou@163.com" class="auth_mail" title="E-mail the corresponding author} ; Jian Xiong^d ; ^b ; ^{xj0918@163.com" class="auth_mail" title="E-mail the corresponding author} ; Yao-rong Dong^a ; ^{1067@szy.sh.cn" class="auth_mail" title="E-mail the corresponding author} ; Chen Yan^b ; ^a ; ^{chen_yan@urmc.rochester.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Higenamine ; 1-[(4-hydroxyphenyl)methyl]-1 ; 2 ; 3 ; 4-tetrahydroisoquinoline-6 ; 7-diol ; I/R ; ischemia/reperfusion ; β-AR ; β-adrenergic receptor ; AC ; adenylyl cyclase ; cAMP ; cyclic adenosine monophosphate ; PKA ; protein kinase A ; ECC ; excitation-contraction coupling ; PTX ; pertussis toxin ; PI3K ; phosphatidyl inositol-3 kinase ; HO-1 ; heme oxygenase-1 ; NRVMs ; neonatal rat ventricular myocytes ; DMEM ; Dulbecco&rsquo ; s Modified Eagle Medium ; FBS ; fetal bovine serum ; Ara-C ; cytosine arabinoside ; ITS ; insulin&nda
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：104
• 期：Complete
• 页码：115-123
• 全文大小：2794 K

文摘

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.