Empagliflozin improves cardiac mitochondrial function and survival through energy regulation in a murine model of heart failure
Abstract
BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been demonstrated to have beneficial effects on HF in large clinical trials; however, the mechanisms remain to be elucidated. The aim of this study was to clarify the mechanisms by which empagliflozin, one of SGLT2 inhibitors, affects heart failure.
METHOD AND RESULTS: Eight-week-old male mice deficient for heart and skeletal muscle-specific manganese superoxide dismutase (MnSOD-cKO mice), a murine model of dilated cardiomyopathy, were given food mixed with or without 10 mg/kg empagliflozin for 7 weeks and evaluated. Both the survival rate and cardiac fibrosis were significantly improved in the empagliflozin group. The capacity for oxidative phosphorylation in cardiac mitochondria was significantly upregulated as measured with Oxygraph-2k respirometer, and blood lactate levels produced by anaerobic metabolism were significantly lower in the empagliflozin group. Energy expenditure was significantly improved in the empagliflozin group, measured by respiratory gas analysis, with a concomitant reduction in serum leptin concentration and increase in food intake. A moderate amount of glucose was excreted in urine in the empagliflozin group; however, the available energy substrate in the body nonetheless expanded because of the much higher caloric intake.
CONCLUSIONS: We conclude that empagliflozin improved cardiac mitochondrial function and upregulated energy metabolism even in HF in mice. These findings provide…
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