Activation of CaMKIIδA promotes Ca2+ leak from the sarcoplasmic reticulum in cardiomyocytes of chronic heart failure rats

• 来源期刊: 中国药理学报（英文版）
• 关键词: chronic heart failure cardiomyocyte Ca2+/calmodulin-dependent protein kinase Ⅱ ryanodine receptors sarcoplasmic reticulum sarcoplasmic reticulum calcium ATPase 2a Ca2+ leak
• 年，卷（期）: 2018,（10）
• 页码范围: 1604-1612
• 页数: 9页
• 语种: 英文
• DOI: 10.1038/aps.2018.20

摘要

Activation of the Ca2+/calmodulin-dependent protein kinase Ⅱ isoform δA (CaMKIIδA) disturbs intracellular Ca2+ homeostasis in cardiomyocytes during chronic heart failure (CHF).We hypothesized that upregulation of CaMKIIδA in cardiomyocytes might enhance Ca2+ leak from the sarcoplasmic reticulum (SR) via activation of phosphorylated ryanodine receptor type 2 (P-RyR2) and decrease Ca2+ uptake by inhibition of SR calcium ATPase 2a (SERCA2a).In this study,CHF was induced in rats by ligation of the left anterior descending coronary artery.We found that CHF caused an increase in the expression of CaMKIIδA and P-RyR2 in the left ventricle (LV).The role of CaMKIIδA in regulation of P-RyR2 was elucidated in cardiomyocytes isolated from neonatal rats in vitro.Hypoxia induced upregulation of CaMKIIδA and activation of P-RyR2 in the cardiomyocytes,which both were attenuated by knockdown of CaMKIIδA.Furthermore,we showed that knockdown of CaMKIIδA significantly decreased the Ca2+ leak from the SR elicited by hypoxia in the cardiomyocytes.In addition,CHF also induced a downregulation of SERCA2a in the LV of CHF rats.Knockdown of CaMKIIδA normalized hypoxia-induced downregulation of SERCA2a in cardiomyocytes in vitro.The results demonstrate that the inhibition of CaMKIIδA may improve cardiac function by preventing SR Ca2+ leak through downregulation of P-RyR2 and upregulation of SERCA2a expression in cardiomyocytes in CHF.