Pharmacological activation of estrogenic receptor G protein-coupled receptor 30 attenuates angiotensin II-induced atrial fibrosis in ovariectomized mice by modulating TGF-β1/smad pathway

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Abstract
Background G-protein-coupled ER (GPR30) plays an important role in cardioprotection. Recent studies have shown that the GPR30-specific agonist G-1 reduces the degree of myocardial fibrosis in rats with myocardial infarction, reduces the morbidity associated with atrial fibrillation, and inhibits the proliferation of cardiac fibroblasts in animal experiments. Nevertheless, the underlying mechanism of myocardial fibrosis and atrial fibrillation remains unclear. In this study, we explored the mechanism underlying the effect of GPR30 on atrial fibrosis and atrial fibrillation in OVX mice. Methods We established an animal model of atrial fibrillation induced by Ang II (derived from OVX C57BL/6 female mice) and observed the role of G-1 in cardiac function by echocardiography, hemodynamics, morphology and fibrosis-related and apoptosis-related protein expression by Masson's trichrome, immunofluorescence, western blotting and TUNEL staining. Results Echocardiography and body surface ECG showed that G-1 combined with Ang II significantly reduced atrial fibrosis and atrial fibrillation compared to Ang II alone. The G-1 treatment group exhibited changes in the mRNA and protein expression of apoptosis-related genes. Moreover, G-1 treatment also altered the levels of inflammation-related proteins and mRNAs. In primary cultured cardiac fibroblasts (CFSs), proliferation was significantly increased in response to Ang II, and G-1 inhibited cell proliferation and apoptosis. Conclusion GPR30 is a potential therapeutic target for alleviating atrial fibrosis in OVX mice by upregulating Smad7 expression to inhibit the TGF-β/Smad pathway.
Funding Information
  • Hebei Province Science and Technology Support Program (19277757D)
  • Natural Science Foundation of Hebei Province (H2019206715)
  • the Department School Consultation Fund - Science and Technology Innovation Project (2020TXJC06)
  • Key Science and Technology Research Program of Hebei Province (20200117)

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