Gremlin Plays a Key Role in the Pathogenesis of Pulmonary Hypertension
Gremlin Plays a Key Role in the Pathogenesis of Pulmonary Hypertension
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DOI：
10.1161/circulationaha.111.038125
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发表时间：
2012-02-21
期刊：
影响因子：
37.8
通讯作者：
McLoughlin, Paul
中科院分区：
文献类型：
--
作者：
Cahill, Edwina;Costello, Christine M.;McLoughlin, Paul
背景--慢性缺氧性肺部疾病中会出现肺动脉高压，显著恶化发病率和死亡率。在确认BMP受体杂合性突变是罕见的遗传性肺动脉高压的潜在缺陷后，改变的骨形态发生蛋白(BMP)信号在肺动脉高压中的重要作用首次被怀疑。随后，研究表明，在包括缺氧性肺动脉高压在内的常见类型的肺动脉高压中，BMP信号也会减少；然而，这种减少的机制尚未阐明。方法和结果-2种BMP拮抗剂gremlin 1和gremlin 2在肺中的表达高于其他器官，在缺氧性肺动脉高压形成过程中，gremlin 1在小鼠肺内小血管壁上的表达进一步增加。低氧刺激体外培养的人肺微血管内皮细胞分泌gremlin，抑制内皮细胞BMP信号转导和BMP刺激的内皮修复。单倍体缺失的gremlin 1增强了低氧小鼠肺中的BMP信号，并通过减弱血管重塑而降低了肺血管阻力。此外，在特发性肺动脉高压和罕见的遗传性肺动脉高压中，肺内小血管壁上的gremlin增加，其分布提示内皮细胞的定位。结论-这些发现表明gremlin增加在缺氧性肺血管重塑和缺氧性肺动脉高压肺血管阻力增加中起中心作用。肺中高水平的基础gremlin表达可能解释了在肺动脉高压中肺循环对BMP 2型受体杂合突变的独特易感性。(发行量。2012；125：920-930。)
Background-Pulmonary hypertension occurs in chronic hypoxic lung diseases, significantly worsening morbidity and mortality. The important role of altered bone morphogenetic protein (BMP) signaling in pulmonary hypertension was first suspected after the identification of heterozygous BMP receptor mutations as the underlying defect in the rare heritable form of pulmonary arterial hypertension. Subsequently, it was demonstrated that BMP signaling was also reduced in common forms of pulmonary hypertension, including hypoxic pulmonary hypertension; however, the mechanism of this reduction has not previously been elucidated.Methods and Results-Expression of 2 BMP antagonists, gremlin 1 and gremlin 2, was higher in the lung than in other organs, and gremlin 1 was further increased in the walls of small intrapulmonary vessels of mice during the development of hypoxic pulmonary hypertension. Hypoxia stimulated gremlin secretion from human pulmonary microvascular endothelial cells in vitro, which inhibited endothelial BMP signaling and BMP-stimulated endothelial repair. Haplodeficiency of gremlin 1 augmented BMP signaling in the hypoxic mouse lung and reduced pulmonary vascular resistance by attenuating vascular remodeling. Furthermore, gremlin was increased in the walls of small intrapulmonary vessels in idiopathic pulmonary arterial hypertension and the rare heritable form of pulmonary arterial hypertension in a distribution suggesting endothelial localization.Conclusions-These findings demonstrate a central role for increased gremlin in hypoxia-induced pulmonary vascular remodeling and the increased pulmonary vascular resistance in hypoxic pulmonary hypertension. High levels of basal gremlin expression in the lung may account for the unique vulnerability of the pulmonary circulation to heterozygous mutations of BMP type 2 receptor in pulmonary arterial hypertension. (Circulation. 2012; 125:920-930.)