Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates vascular remodeling in MCT-induced pulmonary arterial hypertension

Background Pulmonary arterial hypertension (PAH) is a progressive, devastating vascular disease that eventually leads to right heart failure (RHF). Recent studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) are effective in reducing cardiovascular events in patients with HF, but their efficacy in treating PAH remains uncertain. The aim of this study was to investigate the effects of canagliflozin (CANA), an SGLT2i with mild SGLT1 inhibitory effects, on rats with PAH, as well as its direct impact on pulmonary arterial smooth muscle cells (PASMCs). Methods PAH was induced in rats by subcutaneous injection of monocrotaline (MCT) (40 mg/kg), followed by 4 weeks of treatment with CANA by gavage (30 mg/kg/day) or saline alone. Echocardiography, hemodynamic measurements, and histological staining were performed to evaluate pulmonary vascular and right ventricular (RV) structure and function. The effect of CANA on cell proliferation was further investigated in PASMCs. Platelet-derived growth factor (PDGF)-BB, AMP kinase (AMPK) inhibitor compound C (CC) and siSGLT1 were utilized to explore the molecular regulation mechanism of CANA. Results Pulmonary artery and RV remodeling and dysfunction in PAH were alleviated with CANA, as assessed by echocardiography. Hemodynamic parameters, such as RV systolic pressure, and structural of pulmonary arteriole, including vascular wall thickness and wall area, were reduced by CANA treatment. RV hypertrophy index, cardiomyocyte hypertrophy, and fibrosis were decreased with CANA treatment. In vitro, PASMCs proliferation was inhibited by CANA, regardless of PDGF-BB stimulation. Activation of AMPK was induced by CANA treatment in cultured PASMCs in a time- and concentration-dependent manner. These effects of CANA were attenuated by treatment with CC. Abundant expression of SGLT1 was observed in PASMCs and pulmonary arteries of rats, while SGLT2 expression was undetectable. SGLT1 was increased in response to PDGF-BB stimulation, while PASMCs proliferation was inhibited and beneficial effects of CANA were counteracted by knockdown of SGLT1. Conclusions It is demonstrated for the first time that CANA inhibited the proliferation of PASMCs by regulating SGLT1/AMPK signaling and thus exerted an anti-proliferative effect on MCT-induced PAH. Our research revealed a novel mechanism for the beneficial effects of CANA on pulmonary vasculature.