Department of Biochemistry, Centro de Investigación y de Estudios Avanzados del IPN, Cinvestav-IPN, Mexico City, 07300 Mexico.
Department of Pharmacology, Instituto Nacional de Cardiología "Ignacio Chavez", Mexico City, Mexico.
Cell Calcium. 2020 Nov;91:102267. doi: 10.1016/j.ceca.2020.102267. Epub 2020 Aug 12.
Autonomous Ca/calmodulin-dependent protein kinase II (CaMKII) activation induces abnormal diastolic Ca leak, which leads to triggered arrhythmias in a wide range of cardiovascular diseases, including diabetic cardiomyopathy. In hyperglycemia, Ca handling alterations can be aggravated under stress conditions via the β-adrenergic signaling pathway, which also involves CaMKII activation. However, little is known about intracellular Ca handling disturbances under β-adrenergic stimulation in cardiomyocytes of the prediabetic metabolic syndrome (MetS) model with obesity, and the participation of CaMKII in these alterations. MetS was induced in male Wistar rats by administering 30 % sucrose in drinking water for 16 weeks. Fluo 3-loaded MetS cardiomyocytes exhibited augmented diastolic Ca leak (in the form of spontaneous Ca waves) under basal conditions and that Ca leakage was exacerbated by isoproterenol (ISO, 100 nM). At the molecular level, [H]-ryanodine binding and basal phosphorylation of cardiac ryanodine receptor (RyR2) at Ser2814, a CaMKII site, were increased in heart homogenates of MetS rats with no changes in RyR2 expression. These alterations were not further augmented by Isoproterenol. SERCA pump activity was augmented 48 % in MetS hearts before β-adrenergic stimuli, which is associated to augmented PLN phosphorylation at T17, a target of CaMKII. In MetS hearts. CaMKII auto-phosphorylation (T287) was increased by 80 %. The augmented diastolic Ca leak was prevented by CaMKII inhibition with AIP. In conclusion, CaMKII autonomous activation in cardiomyocytes of MetS rats with central obesity significantly contributes to abnormal diastolic Ca leak, increasing the propensity for β-adrenergic receptor-driven lethal arrhythmias.
自主钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）激活可引起异常的舒张期钙泄漏，这导致广泛的心血管疾病（包括糖尿病心肌病）中发生触发性心律失常。在高血糖情况下，β-肾上腺素能信号通路可使应激条件下的钙处理改变加重，而该信号通路还涉及 CaMKII 的激活。然而，在肥胖的代谢综合征（MetS）模型的心肌细胞中，在β-肾上腺素能刺激下，细胞内钙处理的紊乱及其与 CaMKII 的关系，人们知之甚少。在雄性 Wistar 大鼠中，通过在饮用水中添加 30%的蔗糖诱导 MetS 16 周。Fluo 3 负载的 MetS 心肌细胞在基础条件下表现出增强的舒张期钙泄漏（以自发钙波的形式），而异丙肾上腺素（ISO，100 nM）则加剧了钙泄漏。在分子水平上，MetS 大鼠心脏匀浆中的 [H]-ryanodine 结合和心脏 ryanodine 受体（RyR2）的 Ser2814 处的基础磷酸化（CaMKII 位点）增加，而 RyR2 表达没有变化。异丙肾上腺素没有进一步增加这些改变。在β-肾上腺素能刺激之前，MetS 心脏的 SERCA 泵活性增加了 48%，这与 CaMKII 的靶标 PLN 在 T17 处的磷酸化增加有关。在 MetS 心脏中，CaMKII 自身磷酸化（T287）增加了 80%。用 AIP 抑制 CaMKII 可防止 MetS 大鼠心肌细胞舒张期钙泄漏增加。综上所述，中心性肥胖的 MetS 大鼠心肌细胞中自主 CaMKII 激活显著导致异常的舒张期钙泄漏，增加了由β-肾上腺素能受体驱动的致命性心律失常的倾向。
