Gper Stimulation Attenuates Mitochondrial Dysfunction and Cardiac Dysfunction Pathway in Ovariectomized Mice With Hfpef

Objective: Heart failure with preserved ejection fraction (HFpEF) is prevalent among postmenopausal women and is strongly linked to estrogen deficiency. G protein–coupled estrogen receptor (GPER) has emerged as a mediator of estrogen's non-genomic actions, exerting protective cardiovascular effects. However, its role in the pathogenesis of HFpEF remains unclear. This study aimed to explore whether GPER activation could attenuate mitochondrial dysfunction and cardiac damage in ovariectomized (OVX) mice with HFpEF. Design and method: Circulating GPER levels were measured in postmenopausal women with HFpEF and healthy controls. A correction analysis was performed to assess the associations between GPER and cardiac function. Female C57BL/6J mice underwent ovariectomy and were fed with high-fat diet and L-NAME to induce HFpEF. Mice were treated with the GPER agonist G-1 for 4 weeks. Cardiac function, histological changes, oxidative stress, mitochondrial function and mitophagy were evaluated in vivo and in vitro. Results: Serum GPER levels were significantly higher in postmenopausal women with HFpEF and correlated with NT-proBNP and E/e’. In OVX mice with HFpEF, GPER expression was upregulated. G-1 markedly improved diastolic function, reduced myocardial hypertrophy and oxidative stress. Importantly, G-1 restored mitochondrial ATP production, normalized mitochondrial dynamics, and promoted mitophagy both in vivo and in vitro. These beneficial effects were associated with activation of the AMPK/ULK1 pathway. Inhibition of AMPK diminished the protective effects of G-1 in cardiomyocytes. Conclusions: GPER agonist G1 ameliorated mitochondrial dysfunction, promoted mitophagy, and alleviated cardiac diastolic dysfunction in ovariectomized mice with HFpEF, partially through the AMPK/ULK1 pathway. These findings highlight GPER as a potential therapeutic target for postmenopausal women with HFpEF.