Key result
GPR30 agonist G1 attenuates cardiac hypertrophy and fibrosis in pressure-overloaded mice via AKT/mTOR signaling.
Why the study?
Heart failure incidence increases sharply in post-menopausal women, but the role of GPR30 in myocardial hypertrophy in ovariectomized mice had not been investigated.
Does G1 (GPR30 agonist) reduce pressure overload-induced myocardial hypertrophy in ovariectomized mice?
Does G1 (GPR30 agonist) reduce pressure overload-induced myocardial hypertrophy in ovariectomized mice?
p-value: p=<0.05
GPR30 activation by G1 attenuates pressure overload-induced cardiac hypertrophy and fibrosis in ovariectomized mice by inhibiting autophagy via the AKT/mTOR pathway, suggesting a potential therapeutic target for postmenopausal heart failure.
Hypothesis-generating for GPR30 agonism in estrogen-deficient hypertrophy; prospective trials required before any clinical consideration.
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.
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Zhang et al. (2023) studied Pressure overload-induced myocardial hypertrophy. G1 (GPR30 agonist) vs. Vehicle (DMSO:PBS) was evaluated on Cardiac hypertrophy and fibrosis (histological and echocardiographic parameters) (p=<0.05). G1, a specific agonist of GPR30, significantly attenuated cardiac hypertrophy and fibrosis and improved cardiac function in ovariectomized mice with pressure overload by inhibiting autophagy via the AKT/mTOR pathway.
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