title: Downregulation of bone morphogenetic protein receptor axis during HIV-1 and cocaine-mediated pulmonary smooth muscle hyperplasia: implications for HIV-related pulmonary arterial hypertension.
abstract: OBJECTIVE
  Our previous findings support an additive effect of cocaine to HIV infection in the development of pulmonary arteriopathy through enhanced proliferation of human pulmonary smooth muscle cells. We now examined the role of antiproliferative bone morphogenetic protein receptor (BMPR) axis in HIV protein and cocaine-mediated pulmonary smooth muscle hyperplasia.
  
  
  RESULTS
  Stimulation of BMPR axis resulted in attenuation of synergistic increase in the proliferation of human pulmonary arterial smooth muscle cells in response to cocaine and HIV protein, transactivator of transcription (Tat). Interestingly, an increase in mRNA but decrease in protein levels of BMPR with correlated decrease in the activation of Sma- and MAD-related family protein 1/5/8 and Id1 gene expression was observed on combined treatment with cocaine and Tat when compared with the untreated cells at all time points tested. Although longer exposure to either cocaine or Tat alone also resulted in a significant decrease in the BMPR protein expression, the abrogation on combined treatment was still significantly more when compared with that of the monotreatments. Significant increase in mRNA but downmodulation of BMPR protein expression was also observed in the lung extracts from HIV-infected intravenous drug users (HIV+IVDU) when compared with that from HIV-infected non-IVDUs (HIV) or uninfected IVDUs (IVDU). Furthermore, significant decrease in BMPR protein expression was also observed in HIV or IVDUs when compared with normal controls that correlated with in vitro findings on chronic exposure to cocaine or HIV protein alone.
  
  
  CONCLUSIONS
  Simultaneous exposure of pulmonary smooth muscle cells to viral protein(s) and cocaine exacerbates downregulation of BMPR axis that may result in enhanced pulmonary vasculature aberrations in HIV+IVDUs.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine (P.D., A.O'B.-L., N.K.D.) and Department of Molecular and Integrative Physiology (N.K.D.), University of Kansas Medical Center, Kansas City, KS.
authors.forename: Pranjali
authors.initials: P
authors.lastname: Dalvi
authors.forename: Amy
authors.initials: A
authors.lastname: O'Brien-Ladner
authors.forename: Navneet K
authors.initials: NK
authors.lastname: Dhillon
mesh_terms: D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology; D065627:Familial Primary Pulmonary Hypertension; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D015658:HIV Infections / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D015497:HIV-1; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology / Q000821:virology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology / Q000821:virology; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000821:virology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D018765:Dopamine Uptake Inhibitors; D054322:tat Gene Products, Human Immunodeficiency Virus; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; D003042:Cocaine
keywords: HIV-Tat; Nef protein; bone morphogenetic proteins; gp-120; pulmonary vascular remodeling; smooth muscle proliferation cocaine