title: Higenamine protects ischemia/reperfusion induced cardiac injury and myocyte apoptosis through activation of β2-AR/PI3K/AKT signaling pathway.
abstract: 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.
authors.affiliation: Department of Cardiology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China; Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Ave, Box CVRI, Rochester, NY 14642, United States. Electronic address: meipingwu1207@hotmail.com.
authors.forename: Mei-ping
authors.initials: MP
authors.lastname: Wu
authors.affiliation: Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Ave, Box CVRI, Rochester, NY 14642, United States. Electronic address: Yishuai_zhang@outlook.com.
authors.forename: Yi-shuai
authors.initials: YS
authors.lastname: Zhang
authors.affiliation: Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: tazhou@163.com.
authors.forename: Qian-mei
authors.initials: QM
authors.lastname: Zhou
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China; Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Ave, Box CVRI, Rochester, NY 14642, United States. Electronic address: xj0918@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Department of Cardiology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China. Electronic address: 1067@szy.sh.cn.
authors.forename: Yao-rong
authors.initials: YR
authors.lastname: Dong
authors.affiliation: Aab Cardiovascular Research Institute, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Ave, Box CVRI, Rochester, NY 14642, United States; Department of Cardiology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China. Electronic address: chen_yan@urmc.rochester.edu.
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
mesh_terms: D000470:Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D006861:Hydrogen Peroxide; D008297:Male; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000470:Alkaloids; D002316:Cardiotonic Agents; D018343:Receptors, Adrenergic, beta-2; D044005:Tetrahydroisoquinolines; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; C012348:higenamine
keywords: Apoptosis; Beta2-adrenergic receptor; Cardiomyocyte; Higenamine; Higenamine (PubChem CID: 440927); Ischemia/reperfusion