Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates artery remodeling in MCT-induced pulmonary arterial hypertension - 27/04/24
Abstract |
Pulmonary arterial hypertension (PAH) was a devastating disease characterized by artery remodeling, ultimately resulting in right heart failure. The aim of this study was to investigate the effects of canagliflozin (CANA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i) with mild SGLT1 inhibitory effects, on rats with PAH, as well as its direct impact on pulmonary arterial smooth muscle cells (PASMCs). PAH rats were induced by injection of monocrotaline (MCT) (40 mg/kg), followed by four weeks of treatment with CANA (30 mg/kg/day) or saline alone. Pulmonary artery and right ventricular (RV) remodeling and dysfunction in PAH were alleviated with CANA, as assessed by echocardiography. Hemodynamic parameters and structural of pulmonary arteriole, including vascular wall thickness and wall area, were reduced by CANA. RV hypertrophy index, cardiomyocyte hypertrophy, and fibrosis were decreased with CANA treatment. PASMCs proliferation was inhibited by CANA under stimulation by platelet-derived growth factor (PDGF)-BB or hypoxia. Activation of AMP kinase (AMPK) was induced by CANA treatment in cultured PASMCs in a time- and concentration-dependent manner. These effects of CANA were attenuated when treatment with compound C, an AMPK inhibitor. Abundant expression of SGLT1 was observed in PASMCs and pulmonary arteries, while SGLT2 expression was undetectable. SGLT1 increased in response to PDGF-BB or hypoxia stimulation, while PASMCs proliferation was inhibited and beneficial effects of CANA were counteracted by knockdown of SGLT1. Our research 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.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
schematic diagram illustrating the role and mechanism of CANA in inhibiting PASMCs proliferation and alleviating pulmonary artery remodeling in a rat model of PAH induced by MCT.
schematic diagram illustrating the role and mechanism of CANA in inhibiting PASMCs proliferation and alleviating pulmonary artery remodeling in a rat model of PAH induced by MCT.Le texte complet de cet article est disponible en PDF.
Highlights |
• | CANA offers protection against pulmonary artery remodeling in MCT-induced PAH rats. |
• | CANA inhibits the proliferation of PASMCs through the AMPK-dependent pathway. |
• | SGLT1 is involved in the proliferation of PASMCs treated with PDGF-BB and hypoxia. |
• | CANA directly targets SGLT1/AMPK signaling to suppress PASMCs proliferation, exerting an anti-proliferative effect on PAH. |
Keywords : Canagliflozin, Pulmonary arterial hypertension, SGLT2 inhibitors, Proliferation, SGLT1, AMPK
Plan
Vol 174
Article 116505- mai 2024 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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