title: Golgi dysfunction is a common feature in idiopathic human pulmonary hypertension and vascular lesions in SHIV-nef-infected macaques.
abstract: 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.
authors: Rm. 201 Basic Sciences Bldg., Dept. of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA. Pravin_sehgal@nymc.edu
authors: Pravin B
authors: PB
authors: Sehgal
authors: Somshuvra
authors: S
authors: Mukhopadhyay
authors: Kirit
authors: K
authors: Patel
authors: Fang
authors: F
authors: Xu
authors: Sharilyn
authors: S
authors: Almodóvar
authors: Rubin M
authors: RM
authors: Tuder
authors: Sonia C
authors: SC
authors: Flores
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D015693:Gene Products, nef / Q000502:physiology*; D006056:Golgi Apparatus / Q000378:metabolism / Q000473:pathology*; D000077614:Golgi Matrix Proteins; D015658:HIV Infections / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology*; D008251:Macaca / Q000821:virology*; D008565:Membrane Proteins / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000378:metabolism / Q000473:pathology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000302:isolation & purification; D014652:Vascular Diseases / Q000378:metabolism / Q000473:pathology*
chemical_list: D015693:Gene Products, nef; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; C087574:macrogolgin