Aquaporin-1 (AQP1) mediates cardiac oedema and mitochondrial dysfunction in cardiometabolic HFpEF: New insights into the mechanisms of SGLT2 inhibitors

Myocardial oedema contributes significantly to cardiomyocyte dysfunction and death. A 3.5 % increase in water content can result in a 30–50 % reduction in cardiac output. Myocardial oedema is an early complication of prediabetes and is associated with ventricular remodelling and diastolic dysfunction; however, its regulatory mechanisms remain unclear. In this study, we aimed to investigate the role of Aquaporin-1 (AQP1) in myocardial oedema and mitochondrial dysfunction during prediabetes and explore whether the sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) exerts cardioprotective effects by targeting AQP1. Using a high-fat diet-induced hyperinsulinaemic rat model that recapitulates key features of cardiometabolic heart failure with preserved ejection fraction (HFpEF)—including obesity, hypertension, and diastolic dysfunction—along with AQP1 knockout rats and cultured cardiomyocytes, we found that hyperinsulinaemia upregulated cardiac AQP1 expression, leading to myocardial oedema as evidenced by increased myocardial water content and T2-weighted magnetic resonance imaging signals. AQP1 deficiency (in knockout rats) or its knockdown ( in vitro ) significantly attenuated insulin-induced oedema and cardiomyocyte hypertrophy. Mechanistically, AQP1 upregulation disrupted the expression of key ion transporters: Na + /H + exchanger 1, Na + /Ca 2+ exchanger 1, and Na + /K + -ATPase, resulting in intracellular Na + –Ca 2+ overload and mitochondrial dysfunction. EMPA directly bound to AQP1, downregulated its expression, ameliorated myocardial oedema, restored ion transporter balance, and improved mitochondrial function. Our findings indicate that AQP1-driven myocardial oedema is an early critical mechanism of prediabetic myocardial injury, and EMPA partially alleviates this process by downregulating abnormal AQP1 expression. Therefore, targeting AQP1 may represent a novel therapeutic strategy for prediabetic myocardial injury, a key precursor of cardiometabolic HFpEF.