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

Le GUI1, Xin GUO2, Zhe ZHANG1, Hui XU1, Ya-wei JI1, Ren-jun WANG3,4, Jiang-hua ZHU1, Qing-hui CHEN4
1 Institute of Cardiovascular Disease, Department of Cardiology, Nantong University, Nantong 226000, China
2 Department of Urology, Nantong University, Nantong 226000, China
3 Departments of Biotechnology, School of Life Science, Jilin Normal University, Siping 136000, China
4 Department of Kinesiology and Integrative Physiology, Michigan Technological University, Houghton, Michigan 49931, USA
Correspondence to: Jiang-hua ZHU:, Qing-hui CHEN:,
DOI: 10.1038/aps.2018.20
Received: 16 October 2017
Accepted: 19 February 2018
Advance online: 14 June 2018


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.
Keywords: chronic heart failure; cardiomyocyte; Ca2+/calmodulin-dependent protein kinase II; ryanodine receptors; sarcoplasmic reticulum; sarcoplasmic reticulum calcium ATPase 2a; Ca2+ leak

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