安普克
二甲双胍
肺动脉高压
伊诺斯
缺氧性肺血管收缩
前列环素
内科学
内分泌学
医学
蛋白激酶A
AMP活化蛋白激酶
血管收缩
内皮
肺动脉
药理学
一氧化氮
一氧化氮合酶
化学
磷酸化
糖尿病
生物化学
作者
Heba Abdelazeem,Ly Tu,Raphaël Thuillet,Mina Ottaviani,Achraf Boulfrad,Thomas Beck,Amira Senbel,Salma Mani,Yves Castier,Alice Guyard,Alexy Tran-Dinh,Jamel El-Benna,Dan Longrois,Adam M. Silverstein,Christophe Guignabert,Xavier Norel
标识
DOI:10.1016/j.ejphar.2023.175579
摘要
Pulmonary hypertension (PH) is associated with pulmonary vasoconstriction and endothelial dysfunction leading to impaired nitric oxide (NO) and prostacyclin (PGI2) pathways. Metformin, the first line treatment for type 2 diabetes and AMP-activated protein kinase (AMPK) activator, has been recently highlighted as a potential PH treatment. AMPK activation has been reported to improve endothelial function by enhancing endothelial NO synthase (eNOS) activity and to have relaxant effects in blood vessels. In this study, we examined the effect of metformin treatment on PH as well as on NO and PGI2 pathways in monocrotaline (MCT)-injected rats with established PH. Moreover, we investigated the anti-contractile effects of AMPK activators on endothelium-denuded human pulmonary arteries (HPA) from Non-PH and Group 3 PH patients (due to lung diseases and/or hypoxia). Furthermore, we explored the interaction between treprostinil and the AMPK/eNOS pathway. Our results showed that metformin protected against PH progression in MCT rats where it reduced the mean pulmonary artery pressure, pulmonary vascular remodeling and right ventricular hypertrophy and fibrosis compared to vehicle-treated MCT rats. The protective effects on rat lungs were mediated in part by increasing eNOS activity and protein kinase G-1 expression but not through the PGI2 pathway. In addition, incubation with AMPK activators reduced the phenylephrine-induced contraction of endothelium-denuded HPA from Non-PH and PH patients. Finally, treprostinil also augmented eNOS activity in HPA smooth muscle cells. In conclusion, we found that AMPK activation can enhance the NO pathway, attenuate vasoconstriction by direct effects on smooth muscles, and reverse established MCT-induced PH in rats.
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