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This Article Full Text Full Text (PDF) Supplemental Figures and Tables All Versions of this Article: 297/4/L729    most recent 00087.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Sehgal, P. B. Articles by Flores, S. C. PubMed PubMed Citation Articles by Sehgal, P. B. Articles by Flores, S. C.

Golgi dysfunction is a common feature in idiopathic human pulmonary hypertension and vascular lesions in SHIV-nef-infected macaques

Department of ¹Cell Biology and Anatomy, New York Medical College, Valhalla, New York; Department of ²Medicine, New York Medical College, Valhalla, New York; and ; ³Division of Pulmonary and Critical Care Medicine, University of Colorado-Denver, Anschutz Medical Campus, Aurora, Colorado

Submitted 17 March 2009 ; accepted in final form 28 July 2009

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.

pulmonary arterial hypertension; endothelial cells; smooth muscle cells; intra-Golgi tethers; human immuodeficiency virus; giantin; p115; signal transducer and activator of transcription 3

This article has been cited by other articles:

				J. Lee, R. Reich, F. Xu, and P. B. Sehgal Golgi, trafficking, and mitosis dysfunctions in pulmonary arterial endothelial cells exposed to monocrotaline pyrrole and NO scavenging Am J Physiol Lung Cell Mol Physiol, October 1, 2009; 297(4): L715 - L728. [Abstract] [Full Text] [PDF]