Downregulation of bone morphogenetic protein receptor axis during HIV-1 and cocaine-mediated pulmonary smooth muscle hyperplasia: implications for HIV-related pulmonary arterial hypertension

Arterioscler Thromb Vasc Biol. 2013 Nov;33(11):2585-95. doi: 10.1161/ATVBAHA.113.302054. Epub 2013 Sep 5.

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.

Approach and 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.

Keywords: HIV-Tat; Nef protein; bone morphogenetic proteins; gp-120; pulmonary vascular remodeling; smooth muscle proliferation cocaine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Morphogenetic Protein 2 / metabolism
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Bone Morphogenetic Protein Receptors, Type II / metabolism*
  • Cocaine / pharmacology*
  • Dopamine Uptake Inhibitors / pharmacology
  • Down-Regulation / physiology
  • Familial Primary Pulmonary Hypertension
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • HIV Infections / complications*
  • HIV Infections / metabolism
  • HIV Infections / pathology
  • HIV-1*
  • Humans
  • Hyperplasia / metabolism
  • Hyperplasia / pathology
  • Hypertension, Pulmonary* / chemically induced
  • Hypertension, Pulmonary* / pathology
  • Hypertension, Pulmonary* / virology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / pathology
  • Myocytes, Smooth Muscle / virology
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / pathology
  • Pulmonary Artery / virology
  • tat Gene Products, Human Immunodeficiency Virus / genetics
  • tat Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • BMP2 protein, human
  • Bone Morphogenetic Protein 2
  • Dopamine Uptake Inhibitors
  • tat Gene Products, Human Immunodeficiency Virus
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type II
  • Cocaine