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.
摘要：
肺动脉高压（PAH）是一种以动脉重塑为特征的破坏性疾病，最终导致右心衰竭。这项研究的目的是研究canagliflozin（CANA）的作用，一种具有轻度SGLT1抑制作用的钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i），在患有PAH的大鼠上，以及它对肺动脉平滑肌细胞（PASMC）的直接影响。通过注射野百合碱（MCT）（40mg/kg）诱导PAH大鼠，然后用CANA（30mg/kg/天）或单独的生理盐水治疗四周。CANA可减轻PAH的肺动脉和右心室（RV）重塑和功能障碍，通过超声心动图评估。肺动脉的血流动力学参数和结构，包括血管壁厚度和壁面积，被CANA减少了。RV肥大指数,心肌细胞肥大，CANA治疗可减少纤维化。在血小板衍生生长因子（PDGF）-BB或缺氧刺激下，CANA抑制了PASMCs的增殖。通过CANA处理以时间和浓度依赖性方式在培养的PASMC中诱导AMP激酶（AMPK）的激活。用化合物C治疗时，CANA的这些作用减弱，AMPK抑制剂。SGLT1在PASMCs和肺动脉中大量表达,而SGLT2表达检测不到。SGLT1响应PDGF-BB或缺氧刺激而增加，而PASMCs的增殖被抑制，CANA的有益作用被SGLT1的敲低抵消。我们的研究首次表明，CANA通过调节SGLT1/AMPK信号传导抑制PASMC的增殖，从而对MCT诱导的PAH产生抗增殖作用。
