Sodium Glucose Transporter 2 Inhibitor Protects Against Heart Failure With Preserved Ejection Fraction: Preclinical “2‐Hit” Model Reveals Autophagy Enhancement Via AMP‐Activated Protein Kinase/Mammalian Target of Rapamycin Complex 1 Pathway

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Abstract
Background: Heart failure with preserved ejection fraction (HFpEF) is a multifaceted syndrome with high morbidity and mortality. Empagliflozin, an SGLT2 (sodium–glucose cotransporter 2) inhibitor, reduces adverse events in patients with HFpEF regardless of glycemic control. However, the precise cardioprotective mechanisms of SGLT2 inhibitor in HFpEF remain underexplored. Methods and Results: A “2‐hit” mouse model of HFpEF was developed via the high‐fat diet combined with N ω ‐nitro‐L‐arginine methyl ester. Male C57BL/6N mice were assigned to either a control group (n=10) or an HFpEF group (n=20), with the latter receiving empagliflozin (10 mg/kg per day, n=10) or vehicle (n=10) for 8 weeks. Cardiac function, hypertrophy, and fibrosis were evaluated by physiological, biochemical, and histological measurements. Mechanistic analysis, including RNA sequencing, Western blotting, and immunohistochemistry, was conducted. In vitro, H9c2 cardiomyocytes were exposed to angiotensin II and palmitate, followed by empagliflozin treatment. In vivo, empagliflozin treatment improved body weight, blood pressure, glucose tolerance, and reduced cardiac hypertrophy, fibrosis, and diastolic dysfunction in HFpEF mice. Mechanistic analysis revealed that empagliflozin modulated the AMPK (AMP‐activated protein kinase)/mTORC1 (mammalian target of rapamycin complex 1)/autophagy signaling pathway. Specifically, empagliflozin restored the autophagy markers (Beclin1 and LC3‐II [microtubule‐associated protein 1 light chain 3]) and altered the phosphorylation of AMPK, mTOR, and p70S6K (ribosomal protein S6 kinase beta‐1). Inhibition of AMPK or autophagy nullified the antihypertrophic effect of empagliflozin, underscoring the dependence on the AMPK/mTORC1/autophagy pathway. Conclusions: Empagliflozin effectively ameliorates cardiac remodeling and diastolic dysfunction in HFpEF by enhancing autophagy via the AMPK/mTORC1 pathway. These findings elucidate the direct cardioprotective mechanisms of empagliflozin and suggest potential therapeutic molecular targets for HFpEF.

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