title: Hypoxia-inducible factor-1 α/platelet derived growth factor axis in HIV-associated pulmonary vascular remodeling.
abstract: BACKGROUND
  Human immunodeficiency virus (HIV) infected patients are at increased risk for the development of pulmonary arterial hypertension (PAH). Recent reports have demonstrated that HIV associated viral proteins induce reactive oxygen species (ROS) with resultant endothelial cell dysfunction and related vascular injury. In this study, we explored the impact of HIV protein induced oxidative stress on production of hypoxia inducible factor (HIF)-1α and platelet-derived growth factor (PDGF), critical mediators implicated in the pathogenesis of HIV-PAH.
  
  
  METHODS
  The lungs from 4-5 months old HIV-1 transgenic (Tg) rats were assessed for the presence of pulmonary vascular remodeling and HIF-1α/PDGF-BB expression in comparison with wild type controls. Human primary pulmonary arterial endothelial cells (HPAEC) were treated with HIV-associated proteins in the presence or absence of pretreatment with antioxidants, for 24 hrs followed by estimation of ROS levels and western blot analysis of HIF-1α or PDGF-BB.
  
  
  RESULTS
  HIV-Tg rats, a model with marked viral protein induced vascular oxidative stress in the absence of active HIV-1 replication demonstrated significant medial thickening of pulmonary vessels and increased right ventricular mass compared to wild-type controls, with increased expression of HIF-1α and PDGF-BB in HIV-Tg rats. The up-regulation of both HIF-1α and PDGF-B chain mRNA in each HIV-Tg rat was directly correlated with an increase in right ventricular/left ventricular+septum ratio. Supporting our in-vivo findings, HPAECs treated with HIV-proteins: Tat and gp120, demonstrated increased ROS and parallel increase of PDGF-BB expression with the maximum induction observed on treatment with R5 type gp-120CM. Pre-treatment of endothelial cells with antioxidants or transfection of cells with HIF-1α small interfering RNA resulted in abrogation of gp-120CM mediated induction of PDGF-BB, therefore, confirming that ROS generation and activation of HIF-1α plays critical role in gp120 mediated up-regulation of PDGF-BB.
  
  
  CONCLUSIONS
  In summary, these findings indicate that viral protein induced oxidative stress results in HIF-1α dependent up-regulation of PDGF-BB and suggests the possible involvement of this pathway in the development of HIV-PAH.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Kansas Medical Center, Kansas City, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Mermis
authors.forename: Haihua
authors.initials: H
authors.lastname: Gu
authors.forename: Bing
authors.initials: B
authors.lastname: Xue
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Ossama
authors.initials: O
authors.lastname: Tawfik
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
authors.forename: Sonja
authors.initials: S
authors.lastname: Bartolome
authors.forename: Amy
authors.initials: A
authors.lastname: O'Brien-Ladner
authors.forename: Navneet K
authors.initials: NK
authors.lastname: Dhillon
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D000077214:Becaplermin; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000821:virology*; D065627:Familial Primary Pulmonary Hypertension; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism; D015658:HIV Infections / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000235:genetics / Q000821:virology*; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology / Q000821:virology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000098:blood supply*; D055806:Microvessels / Q000201:enzymology / Q000821:virology; D018384:Oxidative Stress / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D011651:Pulmonary Artery / Q000201:enzymology / Q000821:virology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; C497442:HIF1A protein, human; D015699:HIV Envelope Protein gp120; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C514793:gp120 protein, Human immunodeficiency virus 1; D054322:tat Gene Products, Human Immunodeficiency Virus; D000077214:Becaplermin