Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertension
Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertension
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DOI：
10.1111/j.1476-5381.2009.00445.x
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发表时间：
2009-11-01
影响因子：
7.3
通讯作者：
Pacaud, P.
中科院分区：
文献类型：
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作者：
Agard, C.;Rolli-Derkinderen, M.;Pacaud, P.
背景和目的：肺动脉高压（PAH）与肺血管平滑肌细胞的收缩和增殖增加有关。抗糖尿病药物二甲双胍已被证明具有松弛和抗增殖特性。因此，我们研究了二甲双胍在PAH.Experimental方法的影响：二甲双胍的影响进行了分析，在缺氧和野百合碱诱导的PAH大鼠。离体和体外分析进行了肺，肺动脉环和celles.Key结果：在缺氧和野百合碱诱导的PAH，平均肺动脉压和右心肥大的变化几乎正常化二甲双胍治疗（100毫克中心点公斤-1中心点天-1）。两种PAH实验模型中发生的肺动脉重塑也受到二甲双胍治疗的抑制。在野百合碱诱导的PAH大鼠中，二甲双胍治疗显著增加了存活率。二甲双胍增加PAH大鼠肺动脉内皮型一氧化氮合酶磷酸化，降低Rho激酶活性。这些作用与改善卡巴胆碱引起的肺动脉舒张和减少苯肾上腺素引起的肺动脉收缩有关。此外，二甲双胍可抑制丝裂原活化蛋白激酶活化，并显著降低PAH期间的肺动脉细胞增殖。在体外，二甲双胍直接抑制肺动脉平滑肌细胞growth.Conclusions和影响：二甲双胍保护PAH，无论起始刺激。这种保护作用可能与其抗重塑特性有关，包括改善内皮功能、血管舒张和抗增殖作用。由于二甲双胍目前用于治疗糖尿病患者，因此评估其作为人类PAH治疗药物的用途应该更容易。
Background and purpose:Pulmonary arterial hypertension (PAH) is associated with increased contraction and proliferation of pulmonary vascular smooth muscle cells. The anti-diabetic drug metformin has been shown to have relaxant and anti-proliferation properties. We thus examined the effect of metformin in PAH.Experimental approach:Metformin effects were analysed in hypoxia- and monocrotaline-induced PAH in rats. Ex vivo and in vitro analyses were performed in lungs, pulmonary artery rings and cells.Key results:In hypoxia- and monocrotaline-induced PAH, the changes in mean pulmonary arterial pressure and right heart hypertrophy were nearly normalized by metformin treatment (100 mg center dot kg-1 center dot day-1). Pulmonary arterial remodelling occurring in both experimental models of PAH was also inhibited by metformin treatment. In rats with monocrotaline-induced PAH, treatment with metformin significantly increased survival. Metformin increased endothelial nitric oxide synthase phosphorylation and decreased Rho kinase activity in pulmonary artery from rats with PAH. These effects are associated with an improvement of carbachol-induced relaxation and reduction of phenylephrine-induced contraction of pulmonary artery. In addition, metformin inhibited mitogen-activated protein kinase activation and strongly reduced pulmonary arterial cell proliferation during PAH. In vitro, metformin directly inhibited pulmonary artery smooth muscle cell growth.Conclusions and implications:Metformin protected against PAH, regardless of the initiating stimulus. This protective effect may be related to its anti-remodelling property involving improvement of endothelial function, vasodilatory and anti-proliferative actions. As metformin is currently prescribed to treat diabetic patients, assessment of its use as a therapy against PAH in humans should be easier.