Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase
Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase
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DOI：
10.1172/jci.insight.97530
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发表时间：
2018-06-07
期刊：
影响因子：
8
通讯作者：
Baldus, Stephan
中科院分区：
文献类型：
--
作者：
Klinke, Anna;Berghausen, Eva;Baldus, Stephan
肺动脉高压（PAH）仍然是一种治疗选择有限且预后不良的疾病。尽管其病因异质性，潜在的统一病理生理学的特点是血管张力增加和肺循环的不良重塑。髓过氧化物酶（MPO）是一种在中性粒细胞中大量表达的酶，具有强有力的血管收缩和促纤维化特性，因此有资格成为这种疾病的潜在贡献者。在这里，我们试图研究MPO是否与PAH的病理生理学有因果关系。对2个独立临床队列的研究显示，PAH受试者的MPO血浆水平升高，可预测不良结局。实验分析表明，在缺氧时，Mpo（-/-）小鼠的右心室压力增加小于WT小鼠。缺氧诱导的Rho激酶通路的激活，一个关键的亚细胞信号通路产生血管收缩和结构性血管重塑，在Mpo（-/-）小鼠中被钝化。静脉输注MPO的小鼠显示Rho激酶活化和右心室压力增加，这可通过Rho激酶抑制剂Y-27632的共输注来预防。在Sugen 5416/缺氧大鼠模型中，MPO抑制剂AZM 198可减轻PAH。目前的数据表明，MPO，Rho激酶的激活和不良肺血管功能之间存在紧密的机制联系，从而指向一个潜在的新的治疗途径。
Pulmonary arterial hypertension (PAH) remains a disease with limited therapeutic options and dismal prognosis. Despite its etiologic heterogeneity, the underlying unifying pathophysiology is characterized by increased vascular tone and adverse remodeling of the pulmonary circulation. Myeloperoxidase (MPO), an enzyme abundantly expressed in neutrophils, has potent vasoconstrictive and profibrotic properties, thus qualifying as a potential contributor to this disease. Here, we sought to investigate whether MPO is causally linked to the pathophysiology of PAH. Investigation of 2 independent clinical cohorts revealed that MPO plasma levels were elevated in subjects with PAH and predicted adverse outcome. Experimental analyses showed that, upon hypoxia, right ventricular pressure was less increased in Mpo(-/-) than in WT mice. The hypoxia-induced activation of the Rho-kinase pathway, a critical subcellular signaling pathway yielding vasoconstriction and structural vascular remodeling, was blunted in Mpo(-/-) mice. Mice subjected to i.v. infusion of MPO revealed activation of Rho-kinase and increased right ventricular pressure, which was prevented by coinfusion of the Rho-kinase inhibitor Y-27632. In the Sugen5416/hypoxia rat model, PAH was attenuated by the MPO inhibitor AZM198. The current data demonstrate a tight mechanistic link between MPO, the activation of Rho-kinase, and adverse pulmonary vascular function, thus pointing toward a potentially novel avenue of treatment.