Objective: To investigate whether testosterone exacerbates cardiac hypertrophy in postmenopausal hypertension through mitochondrial dynamic imbalance, and to clarify the role of the AKT/FoxO1/MUL1–mediated DRP1 SUMOylation pathway using integrated animal and primary cardiomyocyte models.Design and method: A combined in vivo and in vitro experimental study was conducted. Ovariectomized spontaneously hypertensive rats were treated with testosterone to establish a postmenopausal hyperandrogenic hypertrophy model. Cardiac structure and function were evaluated by echocardiography, histological staining, and morphometric analysis. Mitochondrial ultrastructure was assessed in cardiac tissue by transmission electron microscopy. Mechanistic studies were performed in primary cardiomyocytes exposed to dihydrotestosterone. In vitro, mitochondrial morphology and function were assessed using transmission electron microscopy, MitoTracker staining, and measurements of mitochondrial membrane potential, ATP production, and reactive oxygen species. AKT/FoxO1/MUL1 signaling and DRP1 SUMOylation were examined using Western blotting, RT-qPCR, and immunoprecipitation, with targeted genetic modulation applied exclusively in cardiomyocytes. Pharmacological inhibition of mitochondrial fission with Mdivi-1 was evaluated in both models. Results: Testosterone significantly aggravated cardiac hypertrophy and interstitial fibrosis in ovariectomized hypertensive rats, accompanied by impaired cardiac function. Cardiac tissue exhibited marked mitochondrial ultrastructural abnormalities. In primary cardiomyocytes, dihydrotestosterone induced pronounced mitochondrial fragmentation, reduced membrane potential and ATP production, and increased reactive oxygen species generation. These changes were associated with suppressed AKT phosphorylation, enhanced FoxO1 nuclear translocation, upregulated MUL1 expression, and increased DRP1 SUMOylation. Genetic modulation of FoxO1 or MUL1 in cardiomyocytes significantly altered DRP1 SUMOylation levels and mitochondrial morphology, confirming their regulatory roles. Pharmacological inhibition of mitochondrial fission with Mdivi-1 ameliorated mitochondrial dysfunction and attenuated cardiomyocyte hypertrophy in vitro, while partially reversing cardiac remodeling in vivo. Conclusions: Testosterone promotes cardiac hypertrophy in postmenopausal hypertension by inducing mitochondrial dynamic imbalance. AKT/FoxO1/MUL1-mediated DRP1 SUMOylation in cardiomyocytes represents a key mechanistic link, and targeting pathological mitochondrial fission may offer a potential therapeutic strategy for hypertensive cardiac remodeling in postmenopausal women.
Su et al. (Fri,) studied this question.