Pharmacological Stimulation of GPER Reverses Mitochondrial Dysfunction in the Hearts of Ovariectomized Type 2 Diabetic Rats

Postmenopausal diabetic women face an increased risk of cardiovascular diseases due to estrogen deficiency and metabolic dysfunction. Mitochondrial calcium homeostasis is essential for the viability and energy production of cardiomyocytes; however, the regulation of this process in estrogen‐deficient diabetic hearts is not well understood. This study aimed to explore the effects of activating the G protein‐coupled estrogen receptor 1 (GPER) on cardiac mitochondrial calcium regulation via the mitochondrial calcium uniporter (MCU) in ovariectomized rats with type 2 diabetes (OVX‐T2D). T2D was induced using a high‐fat diet combined with a single dose of streptozotocin (30 mg/kg). The animals were divided into three groups: OVX, OVX + T2D, and OVX + T2D treated with the GPER agonist G1. Our findings indicate that GPER activation significantly increased MCU expression in the heart, mediated by the cAMP/PKA/CREB signaling cascade. This increase was associated with enhanced activity of tricarboxylic acid (TCA) cycle enzymes (PDH and α‐KGDH) and improved mitochondrial ATP production. Additionally, G1 treatment reduced oxidative stress markers (MDA) and increased the activity of antioxidant enzymes (SOD), suggesting a better mitochondrial redox balance. Notably, GPER stimulation also suppressed caspase‐3 expression, indicating a reduction in apoptosis within cardiac tissue. These results demonstrate that GPER activation restores mitochondrial calcium uptake and enhances mitochondrial function in the diabetic postmenopausal heart. This study highlights a novel regulatory mechanism where GPER enhances cardiac mitochondrial resilience through MCU upregulation and related metabolic and antiapoptotic pathways. Targeting GPER may emerge as a promising therapeutic strategy for alleviating diabetic cardiomyopathy in postmenopausal women.