<br>Canagliflozin 通过调节 SGLT1/AMPK 信号传导抑制 PASMC 增殖并减弱 MCT 诱导的肺动脉高压中的动脉重塑,Biomedicine & Pharmacotherapy

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Canagliflozin 通过调节 SGLT1/AMPK 信号传导抑制 PASMC 增殖并减弱 MCT 诱导的肺动脉高压中的动脉重塑
Biomedicine & Pharmacotherapy ( IF 6.9 ) Pub Date : 2024-04-04 , DOI: 10.1016/j.biopha.2024.116505
Xiaojun Chen ₁ , Xing Yu ₁ , Guili Lian ₁ , Huibin Tang ₁ , Yan Yan ₁ , Gufeng Gao ₁ , Bangbang Huang ₁ , Li Luo ₁ , Liangdi Xie ₁

Affiliation

肺动脉高压（PAH）是一种破坏性疾病，其特征是动脉重塑，最终导致右心衰竭。本研究的目的是研究卡格列净 (CANA)（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)）对 PAH 大鼠的作用，以及其对肺动脉平滑肌细胞的直接影响。 PASMC）。通过注射野百合碱 (MCT) (40 mg/kg) 诱导 PAH 大鼠，然后用 CANA (30 mg/kg/天) 或单独生理盐水治疗 4 周。根据超声心动图评估，CANA 可以减轻 PAH 中的肺动脉和右心室 (RV) 重塑和功能障碍。 CANA 降低了血流动力学参数和肺小动脉的结构，包括血管壁厚度和壁面积。 CANA 治疗后，RV 肥大指数、心肌细胞肥大和纤维化均有所降低。在血小板衍生生长因子（PDGF）-BB或缺氧刺激下，CANA抑制PASMCs增殖。在培养的 PASMC 中，CANA 处理以时间和浓度依赖性方式诱导 AMP 激酶 (AMPK) 的激活。当用 AMPK 抑制剂化合物 C 治疗时，CANA 的这些作用会减弱。在 PASMC 和肺动脉中观察到 SGLT1 的大量表达，而 SGLT2 的表达未检测到。 SGLT1 因 PDGF-BB 或缺氧刺激而增加，而 PASMC 增殖受到抑制，并且 CANA 的有益作用因 SGLT1 的敲低而被抵消。我们的研究首次证明CANA通过调节SGLT1/AMPK信号传导抑制PASMCs增殖，从而对MCT诱导的PAH发挥抗增殖作用。

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

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.

更新日期：2024-04-04

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