Dapagliflozin Attenuates Trans-Aortic Constriction-Induced Heart Failure and Fibrosis via FGF21 Signaling Pathway

Abstract

Heart failure has a 1% to 2% prevalence rate among the general adult population, despite the advancement in diagnosis and treatment. Cardiac fibrosis, characterized by the conversion of fibroblasts to myofibroblasts, is central to heart failure. Currently, the drugs used to treat HF include, Renin angiotensin aldosterone system (RAAS) inhibition, β-blockers and angiotensin receptor neprilysin inhibitors. In addition to its glucose-lowering effects, sodium-glucose cotransporter 2 (SGLT2) inhibitors have also displayed cardioprotective effects. However, their mechanisms of action are yet to be elucidated. This study aimed to evaluate the potential involvement of the FGF21 signaling pathway on the cardioprotective effects of the SGLT2 inhibitor, Dapagliflozin (DAPA), using in vivo heart failure and in vitro fibrosis models. Mice were randomly assigned to either sham or transverse-aortic constriction (TAC) surgery to induce heart failure. Following surgery, mice progressing towards heart failure were gavaged daily with either vehicle or DAPA (1 mg/kg/day) for 4 weeks. For the in vitro experimental model, H9c2 cells were pre-treated with DAPA or rmFGF21 for 24 hours and incubated with TGF-β1 (10 ng/ml) for 24 hours. In the case of the depletion experiment, cells were transfected first with FGF21 siRNA for 48 hours and then treated with the chemicals. Treatment with DAPA improved cardiac function markers such as fractional shortening (FS), ejection fraction (EF), left ventricular end-systolic as well as diastolic diameter and LV mass in a pressure overload induced mice model of heart failure. Similarly, the levels of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), IL-6, Fibronectin and Type I Collagen decreased after the treatment with DAPA in the mice model of heart failure. Furthermore, pre-treatment with DAPA attenuated TGF-β induced fibrosis; however, the effect of DAPA was partially inhibited by FGF21 siRNA in H9c2 cardiomyocytes.