Leptin signalling system as a target for pulmonary arterial hypertension therapy
Leptin signalling system as a target for pulmonary arterial hypertension therapy
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DOI：
10.1183/09031936.00193014
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发表时间：
2015-04-01
影响因子：
24.3
通讯作者：
Guignabert, Christophe
中科院分区：
文献类型：
--
作者：
Huertas, Alice;Tu, Ly;Guignabert, Christophe
肺动脉平滑肌细胞（PA-SMC）过度增殖和血管周围炎症导致肺动脉高压（PAH）进展，但它们不是目前治疗的特异性靶点。由于瘦素（leptin，Ob）及其主要受体ObR-b参与全身性血管细胞增殖和炎症反应，因此我们质疑靶向Ob/ObR-b轴是否是治疗PAH的有效抗增殖和抗炎策略。5），我们证明了肺内皮细胞（P-EC）过度产生Ob和PA-SMC过度表达ObR-b。此外，我们获得的证据表明，OB促进人PA-SMCs在体外增殖，并增加右心室收缩压在OB处理的小鼠在慢性缺氧诱导的肺动脉高压（PH）模型。使用人类细胞，我们还表明，Ob导致单核细胞活化，并增加细胞粘附分子在P-ECs的表达水平。我们还发现，Ob/ObR-b轴有助于PH敏感性通过使用ObR缺陷大鼠，其显示不太严重的缺氧诱导的PH（肺血流动力学，动脉肌化，PA-SMC增殖和血管周围炎症）。重要的是，我们证明了两种治疗策略的有效性，使用可溶性OB中和剂和二氯醋酸盐在缺氧诱导的PH。我们在这里证明，OB/ObR-b轴可能代表PAH的抗增殖和抗炎目标。
Excessive proliferation of pulmonary arterial smooth muscle cells (PA-SMCs) and perivascular inflammation lead to pulmonary arterial hypertension (PAH) progression, but they are not specifically targeted by the current therapies. Since leptin (Ob) and its main receptor ObR-b contribute to systemic vascular cell proliferation and inflammation, we questioned whether targeting Ob/ObR-b axis would be an effective antiproliferative and anti-inflammatory strategy against PAH.In idiopathic PAH (iPAH), using human lung tissues and primary cell cultures (early passages. 5), we demonstrate that pulmonary endothelial cells (P-ECs) over produce Ob and that PA-SMCs overexpress ObR-b. Furthermore, we obtain evidence that Ob enhances proliferation of human PA-SMCs in vitro and increases right ventricular systolic pressure in Ob-treated mice in the chronic hypoxia-induced pulmonary hypertension (PH) model. Using human cells, we also show that Ob leads to monocyte activation and increases cell adhesion molecule expression levels in P-ECs. We also find that Ob/ObR-b axis contributes to PH susceptibility by using ObR-deficient rats, which display less severe hypoxia-induced PH (pulmonary haemodynamics, arterial muscularisation, PA-SMC proliferation and perivascular inflammation). Importantly, we demonstrate the efficacy of two curative strategies using a soluble Ob neutraliser and dichloroacetate in hypoxia-induced PH.We demonstrate here that Ob/ObR-b axis may represent anti-proliferative and anti-inflammatory targets in PAH.