Tofogliflozin, a sodium-glucose cotransporter 2 inhibitor, improves pulmonary vascular remodeling due to left heart disease in mice

Group 2 pulmonary hypertension (PH) represents PH caused by left heart disease (PH-LHD). LHD induces left-sided filling and PH, finally leading to pulmonary vascular remodeling. Tofogliflozin (TOFO) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used in the treatment of diabetes. Recent studies have shown that SGLT2 inhibitors have beneficial effects on heart failure, but the effects of SGLT2 inhibitors on PH-LHD remain unclear. We hypothesized that TOFO has protective effects against pulmonary vascular remodeling in PH-LHD mice.We generated two murine models of PH-LHD: a transverse aortic constriction (TAC) model; and a high-fat diet (HFD) model. C57BL/6J mice were subjected to TAC and treated with TOFO (3 mg/kg/day) for 3 weeks. AKR/J mice were fed HFD and treated with TOFO (3 mg/kg/day) for 20 weeks. We then measured physical data and right ventricular systolic pressure (RVSP) and performed cardiography. Human pulmonary artery smooth muscle cells (PASMCs) were cultured and treated with TOFO.Mice treated with TOFO demonstrated increased urine glucose levels. TAC induced left ventricular hypertrophy and increased RVSP. TOFO treatment improved RVSP. HFD increased body weight (BW) and RVSP compared with the normal chow group. TOFO treatment ameliorated increases in BW and RVSP induced by HFD. Moreover, PASMCs treated with TOFO showed suppressed migration.TOFO treatment ameliorated right heart overload and pulmonary vascular remodeling for PH-LHD models, suggesting that SGLT2 inhibitors are effective for treating PH-LHD.