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⁺/CA²⁺ exchanger 1, and Na⁺/K⁺-ATPase, resulting in intracellular Na⁺-Ca²⁺ 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.