Empagliflozin Disrupts a Tnfrsf12a-Mediated Feed Forward Loop That Promotes Left Ventricular Hypertrophy
Abstract
PURPOSE: Although the cardioprotective benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors are now widely appreciated, the mechanisms underlying these benefits remain unresolved. Tumor necrosis factor receptor superfamily member 12a (Tnfrsf12a) is a receptor for tumor necrosis factor superfamily member 12 (Tnfsf12). Tnfrsf12a is highly inducible and plays a key role in the development of cardiac hypertrophy and heart failure. Here we set out to determine if SGLT2 inhibition affects the Tnfsf12/Tnfrsf12a system in the stressed myocardium.
METHODS: C57BL/6N mice that had undergone sham or transverse aortic constriction (TAC) surgery were treated with either the SGLT2 inhibitor empagliflozin (400 mg/kg diet; 60-65 mg/kg/day) or standard chow alone and were followed for 8 weeks. Tnfrsf12a expression in mouse hearts was assessed by in situ hybridization, qRT-PCR, and immunoblotting.
RESULTS: Left ventricular (LV) mass, end-systolic volume, and end-diastolic volume were all increased in TAC mice and were significantly lower with empagliflozin. Myocyte hypertrophy and interstitial fibrosis in TAC hearts were similarly attenuated with empagliflozin. Tnfrsf12a expression was upregulated in mouse hearts following TAC surgery but not in the hearts of empagliflozin-treated mice. In cultured cardiomyocytes, Tnfrsf12a antagonism attenuated the increase in cardiomyocyte size that was induced by phenylephrine.
CONCLUSION: Empagliflozin attenuates LV enlargement in mice with…
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