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.

中文翻译：

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CaMKIIδA的激活促进了慢性心力衰竭大鼠心肌细胞肌浆网中Ca2 +的泄漏。

Ca ²⁺ /钙调蛋白依赖性蛋白激酶II亚型δA（CaMKIIδA）的激活会扰乱慢性心力衰竭（CHF）期间心肌细胞的细胞内Ca ²⁺稳态。我们假设，心肌细胞中CaMKIIδA的上调可能通过激活2型磷酸化ryanodine受体（P-RyR2）增强Ca ²⁺从肌浆网（SR）的渗漏并降低Ca ²⁺通过抑制SR钙ATPase 2a（SERCA2a）摄取。在这项研究中，通过结扎左冠状动脉前降支在大鼠中诱发CHF。我们发现CHF导致左心室（LV）中CaMKIIδA和P-RyR2的表达增加。在体外从新生大鼠分离的心肌细胞中阐明了CaMKIIδA在调节P-RyR2中的作用。缺氧诱导心肌细胞中CaMKIIδA的上调和P-RyR2的激活，两者均被敲低了CaMKIIδA的作用。此外，我们证明了敲低CaMKIIδA会显着降低Ca ²⁺心肌细胞缺氧引起的SR泄漏。此外，CHF还诱导了CHF大鼠左室SERCA2a的下调。体外，CaMKIIδA的敲低使缺氧诱导的心肌细胞中SERCA2a的下调正常化。结果表明，CaMKIIδA的抑制可通过下调P-RyR2和上调CHF心肌细胞中SERCA2a的表达来防止SR Ca ²⁺泄漏，从而改善心脏功能。