Golgi dysfunction is a common feature in idiopathic human pulmonary hypertension and vascular lesions in SHIV-nef-infected macaques.
Golgi dysfunction is a common feature in idiopathic human pulmonary hypertension and vascular lesions in SHIV-nef-infected macaques.
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DOI：
10.1152/ajplung.00087.2009
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发表时间：
2009-10
期刊：
影响因子：
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通讯作者：
P. Sehgal;Somshuvra Mukhopadhyay;K. Patel;Fang Xu;S. Almodovar;R. Tuder;S. Flores
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文献类型：
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作者：
P. Sehgal;Somshuvra Mukhopadhyay;K. Patel;Fang Xu;S. Almodovar;R. Tuder;S. Flores
高尔基体功能障碍是野百合碱诱导的肺动脉高压（PAH）的一种机制。在本研究中，我们讨论了高尔基体功能障碍是否可能发生在肺血管细胞在特发性PAH（IPAH），以及是否有可能是一个因果关系之间的运输功能障碍和PAH的血管病变。与对照组相比，IPAH患者（n = 6）的人肺组织中高尔基体系链giantin和p115的定量免疫染色显示，在IPAH的增殖性、闭塞性和丛状病变中，血管细胞中的giantin和p115携带囊泡成分在细胞质中显著分散，并且每个细胞中这些高尔基体系链/基质蛋白的量增加。因果关系的问题是接近遗传手段使用人类免疫缺陷病毒（HIV）-Nef，一种蛋白质，破坏内吞和trans-Golgi贩运。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。将SIV-nef感染的猕猴（n = 4）的Giantin和p115水平及其在肺血管细胞中的亚细胞分布与SIV感染的猕猴（n = 3）和未感染的猕猴对照进行比较。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。具体而言，HIV-Nef阳性细胞显示giantin、p115和激活的转录因子PY-STAT 3增加。这些数据代表了IPAH中高尔基体功能障碍假说的第一次检验，并将贩运和高尔基体破坏置于猕猴模型中肺血管病的因果关系链中。
Golgi dysfunction has been previously investigated as a mechanism involved in monocrotaline-induced pulmonary hypertension (PAH). In the present study, we addressed whether Golgi dysfunction might occur in pulmonary vascular cells in idiopathic PAH (IPAH) and whether there might be a causal relationship between trafficking dysfunction and vasculopathies of PAH. Quantitative immunostaining for the Golgi tethers giantin and p115 on human lung tissue from patients with IPAH (n = 6) compared with controls demonstrated a marked cytoplasmic dispersal of giantin- and p115-bearing vesicular elements in vascular cells in the proliferative, obliterative, and plexiform lesions in IPAH and an increase in the amounts of these Golgi tethers/matrix proteins per cell. The causality question was approached by genetic means using human immunodeficiency virus (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 nonchimeric SIV virus containing the endogenous SIV-nef gene, displayed pulmonary arterial vasculopathies similar to those in human IPAH. Giantin and p115 levels and their subcellular distribution in pulmonary vascular cells in lungs of SHIV-nef infected macaques (n = 4) were compared with SIV-infected (n = 3) and an uninfected macaque control. Only macaques infected with chimeric SHIV-nef showed pulmonary vascular lesions containing cells with dramatic cytoplasmic dispersal and an increase in giantin and p115. Specifically, the HIV-Nef-positive cells showed increased giantin, p115, and the activated transcription factor PY-STAT3. These data represent the first test of the Golgi dysfunction hypothesis in IPAH and place trafficking and Golgi disruption in the chain of causality of pulmonary vasculopathies in the macaque model.