Department of TCM, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
Department of Biochemistry, College of Basic Medicine, Third Military Medical University, Chongqing, China.
J Cardiovasc Pharmacol. 2020 Aug;76(2):246-254. doi: 10.1097/FJC.0000000000000844.
Cardiac hypertrophy causes heart failure and is associated with hyperglycemia in patients with diabetes mellitus. Mibefradil, which acts as a T-type calcium channel blocker, exerts beneficial effects in patients with heart failure. In this study, we explored the effects and mechanism of mibefradil on high-glucose-induced cardiac hypertrophy in H9c2 cells. H9c2 cells were incubated in a high-glucose medium and then treated with different concentrations of mibefradil in the presence or absence of the Akt inhibitor MK2206 or mTOR inhibitor rapamycin. Cell size was evaluated through immunofluorescence, and mRNA expression of cardiac hypertrophy markers (atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain) was assessed by using quantitative real-time polymerase chain reaction. Changes in the expression of p-PI3K, p-Akt, and p-mTOR were evaluated using Western blotting, and autophagosome formation was detected using transmission electron microscopy. Our results indicate that mibefradil reduced the size of H9c2 cells, decreased mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain, and decreased the level of autophagic flux. However, MK2206 and rapamycin induced autophagy and reversed the effects of mibefradil on high-glucose-induced H9c2 cells. In conclusion, mibefradil ameliorated high-glucose-induced cardiac hypertrophy by activating the PI3K/Akt/mTOR pathway and inhibiting excessive autophagy. Our study shows that mibefradil can be used therapeutically to ameliorate cardiac hypertrophy in patients with diabetes mellitus.
心肌肥厚导致心力衰竭，并与糖尿病患者的高血糖有关。米贝地尔作为一种 T 型钙通道阻滞剂，对心力衰竭患者有有益的作用。在这项研究中，我们探讨了米贝地尔对 H9c2 细胞高糖诱导的心肌肥厚的作用及机制。将 H9c2 细胞在高糖培养基中孵育，然后在存在或不存在 Akt 抑制剂 MK2206 或 mTOR 抑制剂 rapamycin 的情况下用不同浓度的米贝地尔处理。通过免疫荧光评估细胞大小，并用实时定量聚合酶链反应评估心肌肥厚标志物（心房利钠肽、脑利钠肽和β-肌球蛋白重链）的 mRNA 表达。通过 Western blot 评估 p-PI3K、p-Akt 和 p-mTOR 的表达变化，并通过透射电子显微镜检测自噬体形成。我们的结果表明，米贝地尔减小了 H9c2 细胞的大小，降低了心房利钠肽、脑利钠肽和β-肌球蛋白重链的 mRNA 表达，并降低了自噬通量水平。然而，MK2206 和 rapamycin 诱导自噬并逆转了米贝地尔对高糖诱导的 H9c2 细胞的作用。总之，米贝地尔通过激活 PI3K/Akt/mTOR 通路和抑制过度自噬来改善高糖诱导的心肌肥厚。我们的研究表明，米贝地尔可用于治疗糖尿病患者的心肌肥厚。
