Université Paris Cité and Université Sorbonne Paris Nord, INSERM, LVTS, F-75018, Paris, France; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt.
INSERM UMR_S 999 «Pulmonary Hypertension: Pathophysiology and Novel Therapies», Hôpital Marie Lannelongue, 92350, Le Plessis-Robinson, France; Université Paris-Saclay, Faculté de Médecine, 94270, Le Kremlin-Bicêtre, France.
Eur J Pharmacol. 2023 May 5;946:175579. doi: 10.1016/j.ejphar.2023.175579. Epub 2023 Mar 11.
Pulmonary hypertension (PH) is associated with pulmonary vasoconstriction and endothelial dysfunction leading to impaired nitric oxide (NO) and prostacyclin (PGI) 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 PGI 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 PGI 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.
肺动脉高压（PH）与肺血管收缩和内皮功能障碍有关，导致一氧化氮（NO）和前列环素（PGI）途径受损。二甲双胍是 2 型糖尿病的一线治疗药物和 AMP 激活蛋白激酶（AMPK）激活剂，最近被强调为潜在的 PH 治疗药物。AMPK 激活已被报道通过增强内皮型一氧化氮合酶（eNOS）活性来改善内皮功能，并具有血管舒张作用。在这项研究中，我们研究了二甲双胍治疗对 MCT 注射的 PH 大鼠以及对 PH 大鼠中 NO 和 PGI 途径的影响。此外，我们研究了 AMPK 激活剂对非 PH 和第 3 组 PH 患者（由于肺部疾病和/或缺氧）去内皮人肺动脉（HPA）的抗收缩作用。此外，我们还探讨了曲前列尼尔与 AMPK/eNOS 途径之间的相互作用。我们的结果表明，二甲双胍可预防 MCT 大鼠的 PH 进展，与接受 vehicle 治疗的 MCT 大鼠相比，它降低了平均肺动脉压、肺血管重塑和右心室肥大和纤维化。对大鼠肺的保护作用部分是通过增加 eNOS 活性和蛋白激酶 G-1 表达介导的，但不是通过 PGI 途径。此外，AMPK 激活剂孵育可降低非 PH 和 PH 患者去内皮 HPA 对苯肾上腺素的收缩。最后，曲前列尼尔还增强了 HPA 平滑肌细胞中的 eNOS 活性。总之，我们发现 AMPK 激活可以增强 NO 途径，通过直接作用于平滑肌来减轻血管收缩，并逆转大鼠中已建立的 MCT 诱导的 PH。
