科研之友
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摘要
Activation of the Ca2+/calmodulin-dependent protein kinase II isoform delta A (CaMKIII delta A) disturbs intracellular Ca2+ homeostasis in cardiomyocytes during chronic heart failure (CHF). We hypothesized that upregulation of CaMKIII delta A 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 CaMKIII delta A and P-RyR2 in the left ventricle (LV). The role of CaMKIII delta A in regulation of P-RyR2 was elucidated in cardiomyocytes isolated from neonatal rats in vitro. Hypoxia induced upregulation of CaMKIII delta A and activation of P-RyR2 in the cardiomyocytes, which both were attenuated by knockdown of CaMKIII delta A. Furthermore, we showed that knockdown of CaMKIII delta A 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 CaMKIII delta A normalized hypoxia-induced downregulation of SERCA2a in cardiomyocytes in vitro. The results demonstrate that the inhibition of CaMKIII delta A may improve cardiac function by preventing SR Ca2+ leak through downregulation of P-RyR2 and upregulation of SERCA2a expression in cardiomyocytes in CHF.
