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Pharmacological Stimulation of GPER Reverses Mitochondrial Dysfunction in the Hearts of Ovariectomized Type 2
Nahlah Fahad-Alreshidi1, Refaat A Eid2, Abdullah M K Albloshi3
1Department of Internal Medicine, University of Hail, Hail, Saudi Arabia.
Abstract:
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.
Insights
Activating G protein-coupled estrogen receptor 1 (GPER) improves heart function in diabetic postmenopausal rats by restoring mitochondrial calcium regulation and enhancing energy production. This suggests GPER as a potential therapy for diabetic cardiomyopathy.
Area of Science:
- Cardiovascular Biology
- Endocrinology
- Mitochondrial Medicine
Background:
- Postmenopausal diabetic women have high cardiovascular disease risk due to estrogen deficiency and metabolic issues.
- Mitochondrial calcium homeostasis is vital for heart cell energy and function, but its regulation in diabetic, estrogen-deficient hearts is unclear.
Purpose of the Study:
- To investigate how activating G protein-coupled estrogen receptor 1 (GPER) affects cardiac mitochondrial calcium regulation via the mitochondrial calcium uniporter (MCU).
- To explore the impact of GPER activation on mitochondrial function, metabolism, oxidative stress, and apoptosis in a rat model of type 2 diabetes (T2D) and ovariectomy (OVX).
Main Methods:
- Ovariectomized rats were induced with type 2 diabetes (T2D) using a high-fat diet and streptozotocin.
- Animals were divided into three groups: OVX, OVX+T2D, and OVX+T2D treated with the GPER agonist G1.
- Cardiac mitochondrial calcium regulation, MCU expression, TCA cycle enzyme activity, ATP production, oxidative stress markers, antioxidant enzyme activity, and caspase-3 expression were analyzed.
Main Results:
- GPER activation significantly increased MCU expression in the heart, mediated by the cAMP/PKA/CREB pathway.
- This led to enhanced tricarboxylic acid (TCA) cycle enzyme activity (PDH, α-KGDH) and improved mitochondrial ATP production.
- G1 treatment reduced oxidative stress (MDA), increased antioxidant enzyme activity (SOD), and suppressed caspase-3 expression, indicating reduced apoptosis.
Conclusions:
- GPER activation restores mitochondrial calcium uptake and enhances mitochondrial function in the diabetic postmenopausal heart.
- GPER enhances cardiac mitochondrial resilience through MCU upregulation, improving metabolic and antiapoptotic pathways.
- Targeting GPER presents a promising therapeutic strategy for diabetic cardiomyopathy in postmenopausal women.
