Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Int J Mol Sci. 2023 Jan 4;24(2):904. doi: 10.3390/ijms24020904.
The incidence of heart failure mainly resulting from cardiac hypertrophy and fibrosis increases sharply in post-menopausal women compared with men at the same age, which indicates a cardioprotective role of estrogen. Previous studies in our group have shown that the novel estrogen receptor G Protein Coupled Receptor 30 (GPR30) could attenuate myocardial fibrosis caused by ischemic heart disease. However, the role of GPR30 in myocardial hypertrophy in ovariectomized mice has not been investigated yet. In this study, female mice with bilateral ovariectomy or sham surgery underwent transverse aortic constriction (TAC) surgery. After 8 weeks, mice in the OVX + TAC group exhibited more severe myocardial hypertrophy and fibrosis than mice in the TAC group. G1, the specific agonist of GPR30, could attenuate myocardial hypertrophy and fibrosis of mice in the OVX + TAC group. Furthermore, the expression of LC3II was significantly higher in the OVX + TAC group than in the OVX + TAC + G1 group, which indicates that autophagy might play an important role in this process. An in vitro study showed that G1 alleviated AngiotensionII (AngII)-induced hypertrophy and reduced the autophagy level of H9c2 cells, as revealed by LC3II expression and tandem mRFP-GFP-LC3 fluorescence analysis. Additionally, Western blot results showed that the AKT/mTOR pathway was inhibited in the AngII group, whereas it was restored in the AngII + G1 group. To further verify the mechanism, PI3K inhibitor LY294002 or autophagy activator rapamycin was added in the AngII + G1 group, and the antihypertrophy effect of G1 on H9c2 cells was blocked by LY294002 or rapamycin. In summary, our results demonstrate that G1 can attenuate cardiac hypertrophy and fibrosis and improve the cardiac function of mice in the OVX + TAC group through AKT/mTOR mediated inhibition of autophagy. Thus, this study demonstrates a potential option for the drug treatment of pressure overload-induced cardiac hypertrophy in postmenopausal women.
心力衰竭的发病率主要源于心脏肥大和纤维化，绝经后女性与同龄男性相比急剧增加，这表明雌激素具有心脏保护作用。本课题组前期研究表明，新型雌激素受体 G 蛋白偶联受体 30（GPR30）可减轻缺血性心脏病引起的心肌纤维化。然而，GPR30 在前庭切除术小鼠心肌肥大中的作用尚未得到研究。在这项研究中，双侧卵巢切除术或假手术的雌性小鼠接受了腹主动脉缩窄（TAC）手术。8 周后，OVX+TAC 组小鼠的心肌肥大和纤维化比 TAC 组更严重。G1，GPR30 的特异性激动剂，可减轻 OVX+TAC 组小鼠的心肌肥大和纤维化。此外，与 OVX+TAC+G1 组相比，OVX+TAC 组中 LC3II 的表达明显更高，这表明自噬可能在此过程中起重要作用。一项体外研究表明，G1 减轻了血管紧张素 II（AngII）诱导的肥大，并降低了 H9c2 细胞的自噬水平，如 LC3II 表达和串联 mRFP-GFP-LC3 荧光分析所示。此外，Western blot 结果表明，AngII 组中 AKT/mTOR 通路被抑制，而 AngII+G1 组中该通路被恢复。为了进一步验证机制，在 AngII+G1 组中加入了 PI3K 抑制剂 LY294002 或自噬激活剂雷帕霉素，并用 LY294002 或雷帕霉素阻断了 G1 对 H9c2 细胞的抗肥大作用。总之，我们的结果表明，G1 可通过 AKT/mTOR 介导的自噬抑制来减轻 OVX+TAC 组小鼠的心脏肥大和纤维化，并改善其心功能。因此，这项研究为治疗绝经后女性压力超负荷引起的心脏肥大提供了一种潜在的药物选择。
