Icariin protects cardiomyocytes against ischaemia/reperfusion injury by attenuating sirtuin 1‐dependent mitochondrial oxidative damage

• Published in: British journal of pharmacology Vol. 175; no. 21; pp. 4137 - 4153
• Main Authors: Wu, Bing, Feng, Jian‐yu, Yu, Li‐ming, Wang, Yan‐chun, Chen, Yong‐qing, Wei, Yan, Han, Jin‐song, Feng, Xiao, Zhang, Yu, Di, Shou‐yin, Ma, Zhi‐qiang, Fan, Chong‐xi, Ha, Xiao‐qin
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.11.2018; John Wiley and Sons Inc
• Subjects: Animal models; Animals; Apoptosis; Benzamides - pharmacology; Cardiomyocytes; Cells, Cultured; Computer simulation; Contraction; Coronary artery disease; Creatine; Creatine kinase; Cytochrome c; Drugs, Chinese Herbal - administration & dosage; Drugs, Chinese Herbal - pharmacology; Flavonoids - administration & dosage; Flavonoids - pharmacology; FOXO1 protein; Heart diseases; Herbal medicine; Histone deacetylase; Homeostasis; Ischemia; Male; Malondialdehyde; Membrane potential; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardium; Myocytes, Cardiac - drug effects; Naphthols - pharmacology; Neonates; Oxidation; Oxidative stress; Oxidative Stress - drug effects; Pretreatment; Rats; Rats, Sprague-Dawley; Reperfusion; Research Paper; Research Papers; RNA, Small Interfering - pharmacology; Rodents; siRNA; SIRT1 protein; Sirtuin 1 - antagonists & inhibitors; Sirtuin 1 - metabolism; Superoxide; Superoxide dismutase; Traditional Chinese medicine
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.14457

Background and Purpose Icariin, a major active ingredient in traditional Chinese medicines, is attracting increasing attention because of its unique pharmacological effects against ischaemic heart disease. The histone deacetylase, sirtuin‐1, plays a protective role in ischaemia/reperfusion (I/R) injury, and this study was designed to investigate the protective role of icariin in models of cardiac I/R injury and to elucidate the potential involvement of sirtuin‐1. Experimental Approach I/R injury was simulated in vivo (mouse hearts), ex vivo (isolated rat hearts) and in vitro (neonatal rat cardiomyocytes and H9c2 cells). Prior to I/R injury, animals or cells were exposed to icariin, with or without inhibitors of sirtuin‐1 (sirtinol and SIRT1 siRNA). Key Results In vivo and in vitro, icariin given before I/R significantly improved post‐I/R heart contraction and limited the infarct size and leakage of creatine kinase‐MB and LDH from the damaged myocardium. Icariin also attenuated I/R‐induced mitochondrial oxidative damage, decreasing malondialdehyde content and increasing superoxide dismutase activity and expression of Mn‐superoxide dismutase. Icariin significantly improved mitochondrial membrane homeostasis by increasing mitochondrial membrane potential and cytochrome C stabilization, which further inhibited cell apoptosis. Sirtuin‐1 was significantly up‐regulated in hearts treated with icariin, whereas Ac‐FOXO1 was simultaneously down‐regulated. Importantly, sirtinol and SIRT1 siRNA either blocked icariin‐induced cardioprotection or disrupted icariin‐mediated mitochondrial homeostasis. Conclusions and Implications Pretreatment with icariin protected cardiomyocytes from I/R‐induced oxidative stress through activation of sirtuin‐1 /FOXO1 signalling.