Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes

Abstract

The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin reduces heart failure in diabetes, but underlying mechanisms remain elusive. We hypothesized that empagliflozin could counteract the senescence of cardiac stromal cells (CSC), the action of which limits cardiac damage and cardiac fibrosis in diabetic-like conditions in vitro and in vivo. CSC were isolated from murine heart biopsies (n = 5) through cardiosphere (CSp) formation and incubated for 3 or 48 hours with 5.5 mmol/L normal glucose (NG), high glucose (12-5 and 30.5 mmol/L, HG) or a hyperosmolar control of mannitol (HM) in the presence or absence of empagliflozin 100 nmol/L. The senescent CSC status was verified by β-gal staining and expression of the pro-survival marker Akt (pAkt) and the pro-inflammatory marker p38 (p-P38). The cardiac effects of empagliflozin were also studied in vivo by echocardiography and by histology in a murine model of streptozotocin (STZ)-induced diabetes. Compared to NG, incubations with HG and HM significantly reduced the number of CSps, increased the β-gal-positive CSC and P-p38, while decreasing pAkt, all reversed by empagliflozin (P