Department of Pharmaceutical Toxicology, School of Pharmacy, China Medical University, Shenyang, 110122, China.
Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China.
Biochem Biophys Res Commun. 2020 Jun 11;526(4):960-966. doi: 10.1016/j.bbrc.2020.03.188. Epub 2020 Apr 15.
Intracellular calcium is related to cardiac hypertrophy. The Ca1.2 channel and Ca/calmodulin-dependent protein kinase II (CaMKII) and CaM regulate the intracellular calcium content. However, the differences in CaMKII and CaM in cardiac hypertrophy are still conflicting and are worthy of studying as drug targets. Therefore, in this study, we aim to investigate the roles and mechanism of CaM and CaMKII on Ca1.2 in pathological myocardial hypertrophy. The results showed that ISO stimulation caused SD rat heart and cardiomyocyte hypertrophy. In vivo, the HW/BW, LVW/BW, cross-sectional area, fibrosis ratio and ANP expression were all increased. There were no differences in Ca1.2 channel expression in the in vivo model or the in vitro model, but the ISO stimulation induced channel activity, and the [Ca] increased. The protein expression levels of CaMKII and p-CaMKII were all increased in the ISO group, but the CaM expression level decreased. AIP inhibited ANP, CaMKII and p-CaMKII expression, and ISO-induced [Ca] increased. AIP also reduced HDAC4, p-HDAC and MEF2C expression. However, CMZ did not play a cardiac hypertrophy reversal role in vitro. In conclusion, we considered that compared with CaM, CaMKII may be a much more important drug target in cardiac hypertrophy reversal.
细胞内钙与心肌肥厚有关。Ca1.2 通道和钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）和钙调蛋白调节细胞内钙含量。然而，CaMKII 和钙调蛋白在心肌肥厚中的差异仍存在争议，值得作为药物靶点进行研究。因此，在这项研究中，我们旨在研究 CaM 和 CaMKII 对 Ca1.2 在病理性心肌肥厚中的作用和机制。结果表明，ISO 刺激引起 SD 大鼠心脏和心肌细胞肥大。在体内，HW/BW、LVW/BW、横截面积、纤维化比例和 ANP 表达均增加。在体内模型或体外模型中，Ca1.2 通道表达均无差异，但 ISO 刺激诱导通道活性，[Ca]增加。ISO 组 CaMKII 和 p-CaMKII 的蛋白表达水平均增加，但钙调蛋白表达水平降低。AIP 抑制 ANP、CaMKII 和 p-CaMKII 的表达，并减少 ISO 诱导的[Ca]增加。AIP 还降低了 HDAC4、p-HDAC 和 MEF2C 的表达。然而，CMZ 在体外没有发挥逆转心肌肥厚的作用。总之，我们认为与钙调蛋白相比，CaMKII 可能是心肌肥厚逆转中更重要的药物靶点。
