ISCHEMIA-INDUCED CARDIAC ANGIOGENESIS IS MEDIATED BY CAMKII ACTIVATION

Abstract

Objective: The underlying mechanisms for the coronary angiogenesis remain largely unclear. We investigated the role of CaMKII activation in the ischemia-induced cardiac angiogenesis. Design and method: Repetitive transient ischemia was conducted in C57/BL6 mice to mimic chronic angina by daily multiple episodes (3 times/day) of short time (5 min) occlusion of the left anterior descending coronary artery for consecutive 7 days. Coronary angiogenesis was detected by immunofluorescent staining. RT-qPCR and Western blot analyses were used to detect the mRNA and protein levels of CaMKII, p-CaMKII and VEGF. Primary cardiac microvascular endothelial cells (CMECs) were isolated to investigate the effects of CaMKII inhibition on cell proliferation and migration in hypoxic condition. Results: Angiogenesis was induced in the ischemic myocardium and suppressed by chronic intraperitoneal injection of CaMKII inhibitor KN93. RT-qPCR and Western blot analyses showed that myocardial ischemia induced an increased expression and autophosphorylation of CaMKII. VEGF expression was increased in the ischemia model but blunted by KN93. Moreover, KN93 suppressed the proliferation and migration of cardiac endothelial cells in hypoxic condition in which the protein expression of CaMKII, p-CaMKII and VEGF was increased. Conclusions: CaMKII is an important mediator for the ischemia-induced coronary angiogenesis, in which CaMKII-triggered VEGF expression plays a key role.