Protein trafficking dysfunctions: Role in the pathogenesis of pulmonary arterial hypertension.
Protein trafficking dysfunctions: Role in the pathogenesis of pulmonary arterial hypertension.
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DOI：
10.4103/2045-8932.78097
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发表时间：
2011-01
影响因子：
2.6
通讯作者：
Lee JE
中科院分区：
文献类型：
--
作者：
Sehgal PB;Lee JE
早期的电子显微镜数据显示，在人类和实验模型中，肺动脉高压（PAH）中血管重塑的标志包括肺动脉病变中的空泡化内皮细胞和平滑肌细胞增大，内质网和高尔基体堆积增加。在细胞培养和体内实验中，在野百合碱模型中，我们观察到高尔基体功能和细胞内运输的破坏与捕获不同的囊泡栓系，SNARE和SNAP在扩大的肺动脉内皮细胞（PAECs）和肺动脉平滑肌细胞（PASMCs）的高尔基体膜。其后果包括细胞表面小窝蛋白-1的丢失，STAT 3的过度激活，eNOS的错误定位与细胞表面/小窝NO的减少和运输相关蛋白的低S-亚硝基化。在培养的缺氧PAEC和NO清除的PAEC中也观察到类似的高尔基体系链、SNARE和SNAP功能障碍。引人注目的是，低NO状态促进PAEC有丝分裂和细胞增殖。在特发性PAH（IPAH）的肺血管细胞中也观察到高尔基体功能障碍，表现为IPAH中增殖性、闭塞性和丛状病变细胞中高尔基体系链、巨噬细胞蛋白和p115的细胞质分散和细胞含量增加。通过使用HIV-nef（一种破坏内吞和跨高尔基体运输的蛋白质）的遗传方法，探讨了运输功能障碍和PAH血管病变之间是否存在因果关系的问题。猕猴感染嵌合猴免疫缺陷病毒（SIV）含有HIV-nef基因（SHIV-nef），但不是非嵌合SIV病毒含有内源性SIV-nef基因，显示肺动脉血管病变类似于人类IPAH。只有感染嵌合SHIV-nef的猕猴显示肺血管病变，其中细胞具有显着的细胞质分散和giantin和p115的增加。具体地说，是HIV-nef阳性细胞显示出增加的巨蛋白。阐明这些变化中的每一个如何适应缺氧、NO生物利用度降低、BMPR II突变、PAH发病机制中疾病发生率的调节和性别效应的多因素背景是未来道路的一部分。
Earlier electron microscopic data had shown that a hallmark of the vascular remodeling in pulmonary arterial hypertension (PAH) in man and experimental models includes enlarged vacuolated endothelial and smooth muscle cells with increased endoplasmic reticulum and Golgi stacks in pulmonary arterial lesions. In cell culture and in vivo experiments in the monocrotaline model, we observed disruption of Golgi function and intracellular trafficking with trapping of diverse vesicle tethers, SNAREs and SNAPs in the Golgi membranes of enlarged pulmonary arterial endothelial cells (PAECs) and pulmonary arterial smooth muscle cells (PASMCs). Consequences included the loss of cell surface caveolin-1, hyperactivation of STAT3, mislocalization of eNOS with reduced cell surface/caveolar NO and hypo-S-nitrosylation of trafficking-relevant proteins. Similar Golgi tether, SNARE and SNAP dysfunctions were also observed in hypoxic PAECs in culture and in PAECs subjected to NO scavenging. Strikingly, a hypo-NO state promoted PAEC mitosis and cell proliferation. Golgi dysfunction was also observed in pulmonary vascular cells in idiopathic PAH (IPAH) in terms of a marked cytoplasmic dispersal and increased cellular content of the Golgi tethers, giantin and p115, in cells in the proliferative, obliterative and plexiform lesions in IPAH. The question of whether there might be a causal relationship between trafficking dysfunction and vasculopathies of PAH was approached by genetic means using HIV-nef, a protein that disrupts endocytic and trans-Golgi trafficking. Macaques infected with a chimeric simian immunodeficiency virus (SIV) containing the HIV-nef gene (SHIV-nef), but not the non-chimeric SIV virus containing the endogenous SIV-nef gene, displayed pulmonary arterial vasculopathies similar to those in human IPAH. Only macaques infected with chimeric SHIV-nef showed pulmonary vascular lesions containing cells with dramatic cytoplasmic dispersal and increase in giantin and p115. Specifically, it was the HIV-nef–positive cells that showed increased giantin. Elucidating how each of these changes fits into the multifactorial context of hypoxia, reduced NO bioavailability, mutations in BMPR II, modulation of disease penetrance and gender effects in disease occurrence in the pathogenesis of PAH is part of the road ahead.