Key result
GPER agonist G-1 improves diastolic function and reduces hypertrophy in postmenopausal HFpEF models.
Why the study?
The role of GPER in the pathogenesis of HFpEF remains unclear, motivating an exploration of whether GPER activation could attenuate mitochondrial dysfunction and cardiac damage in ovariectomized mice with HFpEF.
Does the GPER agonist G-1 attenuate mitochondrial dysfunction and cardiac diastolic dysfunction in ovariectomized mice with HFpEF?
Does the GPER agonist G-1 attenuate mitochondrial dysfunction and cardiac diastolic dysfunction in ovariectomized mice with HFpEF?
GPER activation with the agonist G-1 alleviates cardiac diastolic dysfunction and mitochondrial damage in a mouse model of postmenopausal HFpEF via the AMPK/ULK1 pathway, identifying GPER as a potential therapeutic target.
GPER agonism merits clinical investigation in postmenopausal HFpEF; hypothesis-generating and should not yet change practice.
Background 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. Methods 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.
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Qi et al. (2026) studied Heart failure with preserved ejection fraction (HFpEF). GPER agonist G-1 vs. Untreated ovariectomized HFpEF mice / healthy controls was evaluated on Cardiac diastolic function, myocardial hypertrophy, oxidative stress, mitochondrial function, and mitophagy. GPER agonist G-1 treatment for 4 weeks improved diastolic function, reduced hypertrophy, and restored mitochondrial ATP production and mitophagy in ovariectomized mice with HFpEF.
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