Autonomous Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) activation induces abnormal diastolic Ca²⁺ leak, which leads to triggered arrhythmias in a wide range of cardiovascular diseases, including diabetic cardiomyopathy. In hyperglycemia, Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ leak (in the form of spontaneous Ca²⁺ waves) under basal conditions and that Ca²⁺ leakage was exacerbated by isoproterenol (ISO, 100 nM). At the molecular level, [³H]-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 Ca²⁺ 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 Ca²⁺ leak, increasing the propensity for β-adrenergic receptor-driven lethal arrhythmias.

自主 Ca ²⁺ /钙调蛋白依赖性蛋白激酶 II (CaMKII) 激活诱导异常舒张 Ca ²⁺泄漏，这会导致多种心血管疾病（包括糖尿病心肌病）引发心律失常。在高血糖症中，在应激条件下，通过 β-肾上腺素能信号通路可能会加剧Ca ²⁺处理的改变，这也涉及 CaMKII 的激活。然而，对于糖尿病前期代谢综合征 (MetS) 肥胖模型的心肌细胞中 β-肾上腺素能刺激下的细胞内 Ca ²⁺处理障碍以及 CaMKII 参与这些改变知之甚少。

通过在饮用水中施用 30% 蔗糖 16 周，在雄性 Wistar 大鼠中诱导了 MetS。Fluo 3 加载的 MetS 心肌细胞在基础条件下表现出增强的舒张 Ca ²⁺泄漏（以自发 Ca ²⁺波的形式），并且 Ca ²⁺泄漏被异丙肾上腺素（ISO，100 nM）加剧。在分子水平上，[ ³在 MetS 大鼠的心脏匀浆中，H]-兰尼丁受体 (RyR2) 在 CaMKII 位点 Ser2814 处的 H]-兰尼丁结合和基础磷酸化增加，而 RyR2 表达没有变化。异丙肾上腺素没有进一步增强这些改变。在 β-肾上腺素能刺激之前，MetS 心脏中的 SERCA 泵活性增加了 48%，这与 T17（CaMKII 的目标）的 PLN 磷酸化增强有关。在大都会心中。CaMKII 自动磷酸化 (T287) 增加了 80%。用 AIP 抑制 CaMKII 可防止增加的舒张 Ca ²⁺泄漏。综上所述，向心性肥胖MetS大鼠心肌细胞CaMKII自主激活显着导致舒张Ca ²⁺异常 漏，增加了β-肾上腺素能受体驱动的致死性心律失常的倾向。