Activation of CaMKIIδA promotes Ca leak from the sarcoplasmic reticulum in cardiomyocytes of chronic heart failure rats.

Activation of the Ca/calmodulin-dependent protein kinase II isoform δA (CaMKIIδA) disturbs intracellular Ca homeostasis in cardiomyocytes during chronic heart failure (CHF). We hypothesized that upregulation of CaMKIIδA in cardiomyocytes might enhance Ca leak from the sarcoplasmic reticulum (SR) via activation of phosphorylated ryanodine receptor type 2 (P-RyR2) and decrease Ca 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 Ca 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 Ca leak through downregulation of P-RyR2 and upregulation of SERCA2a expression in cardiomyocytes in CHF.