Aberrant chloride intracellular channel 4 expression contributes to endothelial dysfunction in pulmonary arterial hypertension.
Aberrant chloride intracellular channel 4 expression contributes to endothelial dysfunction in pulmonary arterial hypertension.
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DOI：
10.1161/circulationaha.113.006797
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发表时间：
2014-04-29
期刊：
影响因子：
37.8
通讯作者：
Wilkins MR
中科院分区：
文献类型：
--
作者：
Wojciak-Stothard B;Abdul-Salam VB;Lao KH;Tsang H;Irwin DC;Lisk C;Loomis Z;Stenmark KR;Edwards JC;Yuspa SH;Howard LS;Edwards RJ;Rhodes CJ;Gibbs JS;Wharton J;Zhao L;Wilkins MR
氯离子胞内通道4（CLIC 4）在肺动脉高压（PAH）患者重构的肺血管内皮和丛状病变中高度表达。CLIC 4通过内皮管形成调节血管发生。CLIC 4的异常表达可能与PAH的血管病理学有关。CLIC 4蛋白表达在特发性PAH（IPAH）患者的血浆和血液来源的内皮细胞以及3种肺动脉高压大鼠模型的肺血管内皮细胞中增加。CLIC 4基因缺失可明显减轻小鼠慢性缺氧性肺动脉高压的形成。在培养的人肺动脉内皮细胞中，CLIC 4的腺病毒过表达损害肺内皮屏障功能，并增强其存活和血管生成能力，而CLIC 4 shRNA具有抑制作用。类似地，抑制IPAH患者的血液来源的内皮细胞中的CLIC 4表达减弱了这些细胞特有的异常血管生成行为。CLIC 4效应的机制涉及p65介导的核因子-κB活化，随后是缺氧诱导因子-1 α的稳定和血管内皮生长因子和内皮素-1的下游产生增加。CLIC 4表达增加是肺动脉高压内皮功能障碍的早期表现和介导因素。
Chloride intracellular channel 4 (CLIC4) is highly expressed in the endothelium of remodelled pulmonary vessels and plexiform lesions of patients with pulmonary arterial hypertension (PAH). CLIC4 regulates vasculogenesis through endothelial tube formation. Aberrant CLIC4 expression may contribute to the vascular pathology of PAH. CLIC4 protein expression was increased in plasma and blood-derived endothelial cells from patients with idiopathic PAH (IPAH) and in the pulmonary vascular endothelium of 3 rat models of pulmonary hypertension. CLIC4 gene deletion markedly attenuated the development of chronic hypoxia-induced pulmonary hypertension in mice. Adenoviral overexpression of CLIC4 in cultured human pulmonary artery endothelial cells compromised pulmonary endothelial barrier function and enhanced their survival and angiogenic capacity, while CLIC4 shRNA had an inhibitory effect. Similarly, inhibition of CLIC4 expression in blood-derived endothelial cells from patients with IPAH attenuated the abnormal angiogenic behaviour that characterises these cells. The mechanism of CLIC4 effects involves p65-mediated activation of nuclear factor-κB, followed by stabilisation of hypoxia-inducible factor-1α and increased downstream production of vascular endothelial growth factor and endothelin-1. Increased CLIC4 expression is an early manifestation and mediator of endothelial dysfunction in pulmonary hypertension.