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The SGLT2 Inhibitor Empagliflozin Enhances Metabolic Efficiency and Ameliorates Left Ventricular Hypertrophy in Myosin R403Q Mutant Hypertrophic Cardiomyopathy Mice

ABSTRACT: Background: Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and impaired metabolic efficiency. This study investigates the therapeutic potential of the sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) in ameliorating these pathological features in a mouse model carrying the myosin R403Q mutation. Methods: Male mice harboring the R403Q mutation were treated with EMPA for 16 weeks. We utilized multinuclear magnetic resonance spectroscopy (31P, 13C, 23Na MRS), alongside echocardiography, transcriptomic, proteomic, and phosphoproteomic profiling to assess metabolic, structural, and functional changes. Results: EMPA facilitated the coupling of glycolysis with glucose oxidation and normalized elevated intracellular sodium levels. Treatment resulted in a significant reduction in LVH and myocardial fibrosis as evidenced by echocardiography and histopathology. These structural improvements correlated with enhancements in mitochondrial ATP synthesis, fatty acid oxidation (FAO), and branched-chain amino acid (BCAA) catabolism. Furthermore, empagliflozin improved left ventricular diastolic function and contractile reserve, underscored by improved ATP production and reduced energy cost of contraction. Notably, these benefits were linked to downregulation of the mTOR signaling pathway and normalization of myocardial substrate metabolic fluxes. Conclusion: EMPA significantly mitigates structural and metabolic dysfunctions in a mouse model of HCM, underscoring its potential as a therapeutic agent for managing this condition. These findings suggest broader applicability of SGLT2 inhibitors in cardiovascular diseases, including those due to myocardial-specific mutations, warranting further clinical investigation.

ORGANISM(S): Mus musculus

PROVIDER: GSE270093 | GEO | 2025/06/09

REPOSITORIES: GEO

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Project description:Heart Failure with preserved Ejection Fraction (HFpEF) is a major global health problem but there are no effective therapies. The aim of this study was to assess the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian (feline) pressure overload model with HFpEF features. Male domestic short hair cats (n=26, aged 2mo), underwent either a sham procedure (n=5) or aortic constriction (n=21) using a pre-shaped band, resulting in slow-progressive pressure overload during subsequent growth. Two-months post-banding, banded cats were treated daily with either 10mg/kg suberoylanilide hydroxamic acid (b+SAHA) (n=8), an FDA approved pan-HDAC inhibitor, or vehicle (b+veh) (n=8) for 2 months. Echocardiography at 4-months post-banding revealed that b+SAHA animals had a significant reduction in left ventricular hypertrophy (LVH) and LA size vs b+veh animals. Invasively measured left ventricular end-diastolic pressure (LVEDP) and mean pulmonary arterial pressure (mPAP) were significantly elevated in b+veh and significantly reduced by b+SAHA. SAHA speeded ex-vivo myofibril relaxation independent of LVH and this effect correlated with in-vivo indices of LV relaxation. Furthermore, SAHA preserved lung structure, improved lung compliance and oxygenation, reflected by a decrease in alveolar-capillary wall thickness, alveolar-arterial oxygen gradient (A-aDO2), and intrapulmonary shunt. SAHA also reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar-capillary stress failure. Acetylation proteomics revealed that SAHA altered protein acetylation in cat hearts, including histones, many mitochondrial metabolic enzymes involved in electron transport chain, TCA cycle, malate aspartate shuttle and beta oxidation, as well as cytoskeletal proteins important for muscle function. These results suggest that acetylation defects in hypertrophic stress states can be reversed by HDAC inhibitors and may be useful to improve cardiac structure and function in HFpEF patients.

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The SGLT2 Inhibitor Empagliflozin Enhances Metabolic Efficiency and Ameliorates Left Ventricular Hypertrophy in Myosin R403Q Mutant Hypertrophic Cardiomyopathy Mice

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