Dapagliflozin, An SGLT2 Inhibitor, Improves Endothelial Cell Energy Metabolism Through Enhanced Mitochondrial Respiration

Flozins (sodium-glucose cotransporter 2 inhibitors, SGLT2i) are a new class of antidiabetic drugs that reduce cardiovascular mortality and hospitalization rates in heart failure, regardless of type 2 diabetes status. Besides lowering glycemia by inhibiting renal glucose reabsorption, SGLT2 inhibitors may exert sodium-dependent hemodynamic effects and improve cardiomyocyte energy metabolism, substrate preference, and mitochondrial function. However, their impact on endothelial cells remains largely unknown. This study aimed to analyse the effects and mechanisms of SGLT2i on endothelial cell metabolism and function. Mouse cardiac endothelial cells (H5V) were used to test the impact of dapagliflozin on endothelial cell metabolism and function in the presence of hypoxia-mimicking conditions. The concentration of intracellular nucleotides was measured using high-performance liquid chromatography. Mitochondrial and glycolytic activity were assessed using Seahorse XFp, while nitric oxide (NO) production was determined by 4-Amino-5-Methylamino-2',7'-Difluorofluorescein (DAF-FM) fluorescence staining. The effects of dapagliflozin treatment on endothelial NO synthesis were also analysed in patients with chronic heart failure and left ventricular ejection fraction above 40% and C57Bl/6J mice. Dapagliflozin augmented adenosine triphosphate (ATP) levels and the ATP/ADP (adenosine diphosphate) ratio in cultured endothelial cells correlated to increased NO production. Dapagliflozin-treated endothelial cells produced ATP through both mitochondrial respiration and glycolysis. Interestingly, mitochondrial respiration was enhanced, while glycolysis was unaffected in endothelial cells after in vitro dapagliflozin treatment. In a murine model, dapagliflozin doubled the rate of coronary NO synthesis and tended to improve coronary capillary density. In humans with chronic heart failure, 3-month treatment with dapagliflozin revealed many metabolic effects, suggesting potential mechanisms related to nitric oxide homeostasis, mitochondrial function, and L-arginine metabolism. This study demonstrated the beneficial effect of dapagliflozin on endothelial cell metabolism and function. Regulation of endothelial cell bioenergetics may be an undervalued mechanism of SGLT2i to delay heart failure progression and support cardiac regeneration. These may accelerate endothelial-targeted strategies to support heart failure treatment.