Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents
Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents
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DOI：
10.1172/jci35070
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发表时间：
2009-03-01
影响因子：
15.9
通讯作者：
Eddahibi, Saadia
中科院分区：
文献类型：
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作者：
Izikki, Mohamed;Guignabert, Christophe;Eddahibi, Saadia
肺动脉高压（Pulmonary hypertension， PH）是一种以肺动脉SMC （PA-SMC）增生为特征的进行性致死性肺部疾病。导致右侧心力衰竭。来源于肺内皮细胞（P-ECs）的分子事件可能导致PH中PA-SMC增生。因此，我们将培养的人PA-SMC暴露于来自特发性PH （IPH）患者或对照组的P-EC培养基中，发现IPH P-EC培养基比对照P-EC培养基更能促进PA-SMC增殖。与对照组相比，IPH P-ECs培养基中FGF2水平升高，而tgf - β 1、PDGF-BB或EGF水平没有可检测到的差异。在IPH和对照PA-SMCs之间，fgf2诱导的增殖和FGF受体1 (FGFR1) mRNA水平没有差异。使用siRNA敲低P-EC中的FGF2， IPH P-EC培养基的PA-SMC生长刺激作用降低了60%，对照P-EC培养基降低了10%。原位杂交显示FGF2主要在重构血管内皮中过量产生。IPH患者的肺反复静脉注射FGF2- sirna可消除肺中FGF2的产生，从而预防并几乎逆转大鼠PH模型。同样，在同一模型中，SU5402对FGFR1的药理学抑制可逆转已建立的PH。因此，内皮细胞FGF2在IPH中过量产生，并导致SMC增生。在IPH中，确定FGF2作为抗PH新疗法的有希望的靶点。
Pulmonary hypertension (PH) is a progressive, lethal lung disease characterized by pulmonary artery SMC (PA-SMC) hyperplasia. leading to right-sided heart failure. Molecular events originating in pulmonary ECs (P-ECs) may contribute to the PA-SMC hyperplasia in PH. Thus, we exposed cultured human PA-SMC to medium conditioned by P-EC from patients with idiopathic PH (IPH) or controls and found that IPH P-EC-conditioned medium increased PA-SMC proliferation more than control P-EC medium. Levels of FGF2 were increased in the medium of IPH P-ECs over controls, while there was no detectable difference in TGF-beta 1, PDGF-BB, or EGF levels. No difference in FGF2-induced proliferation or FGF receptor type 1 (FGFR1) mRNA levels was detected between IPH and control PA-SMCs. Knockdown of FGF2 in P-EC using siRNA reduced the PA-SMC growth-stimulating effects of IPH P-EC medium by 60% and control P-EC medium by 10%. In situ hybridization showed FGF2 overproduction predominantly in the remodeled vascular endothelium. of lungs from patients with IPH. Repeated intravenous FGF2-siRNA administration abolished lung FGF2 production, both preventing and nearly reversing a rat model of PH. Similarly, pharmacological FGFR1 inhibition with SU5402 reversed established PH in the same model. Thus, endothelial FGF2 is overproduced in IPH and contributes to SMC hyperplasia. in IPH, identifying FGF2 as a promising target for new treatments against PH.