title: Effect of Cocaine on Pulmonary Vascular Remodeling and Hemodynamics in Human Immunodeficiency Virus-Transgenic Rats.
abstract: Human immunodeficiency virus (HIV)-related pulmonary arterial hypertension has been found to be more prevalent in intravenous drug users. Our earlier cell-culture findings reported down-regulation of bone morphogenetic protein receptors (BMPRs) in combination with enhanced proliferation of human pulmonary arterial smooth muscle cells (PASMCs) in the presence of HIV-Trans-activator of transcription (Tat) and cocaine compared with either treatment alone. Here, we report physiologic evidence of significant increases in mean pulmonary arterial pressure in HIV-transgenic (Tg) rats intraperitoneally administered 40 mg/kg body weight cocaine (HIV-cocaine group) once daily for 21 days when compared with HIV-Tg rats given saline (HIV group) or wild-type (WT) Fischer 334 rats treated with (WT-cocaine group) and without cocaine (WT group). In addition, right ventricle systolic pressure was also found to be significantly higher in the HIV-cocaine rats compared with the WT group. Significant down-regulation in protein expression of BMPR-2 and BMPR-1B was observed in total lung extract from HIV-cocaine rats compared with the other three groups. Furthermore, the PASMCs isolated from HIV-cocaine rats demonstrated a higher level of proliferation and lower levels of apoptosis compared with cells isolated from other rat groups. Interestingly, corroborating our earlier cell-culture findings, we observed higher expression of BMPR-2 and BMPR-1B messenger RNA and significantly lower levels of BMPR-2 and BMPR-1B protein in HIV-cocaine PASMCs compared with cells isolated from all other groups. In conclusion, our findings support an additive effect of cocaine and HIV on smooth muscle dysfunction, resulting in enhanced pulmonary vascular remodeling with associated elevation of mean pulmonary arterial pressure and right ventricle systolic pressure in HIV-Tg rats exposed to cocaine.
authors.affiliation: 1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, and.
authors.forename: Pranjali
authors.initials: P
authors.lastname: Dalvi
authors.affiliation: 1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, and.
authors.forename: Leslie
authors.initials: L
authors.lastname: Spikes
authors.affiliation: 1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, and.
authors.forename: Julie
authors.initials: J
authors.lastname: Allen
authors.affiliation: 2 Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Vijayalaxmi G
authors.initials: VG
authors.lastname: Gupta
authors.affiliation: 1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, and.
authors.forename: Himanshu
authors.initials: H
authors.lastname: Sharma
authors.affiliation: 1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, and.
authors.forename: Marion
authors.initials: M
authors.lastname: Gillcrist
authors.affiliation: 1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, and.
authors.forename: Jamison
authors.initials: J
authors.lastname: Montes de Oca
authors.affiliation: 1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, and.
authors.forename: Amy
authors.initials: A
authors.lastname: O'Brien-Ladner
authors.affiliation: 1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, and.|2 Department of Molecular & Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Navneet K
authors.initials: NK
authors.lastname: Dhillon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D003042:Cocaine / Q000009:adverse effects*; D015536:Down-Regulation / Q000187:drug effects; D006678:HIV / Q000187:drug effects / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D015398:Signal Transduction / Q000187:drug effects; D013599:Systole / Q000187:drug effects; D066253:Vascular Remodeling / Q000187:drug effects*; D014764:Viral Proteins / Q000378:metabolism
chemical_list: D014764:Viral Proteins; D052004:Bone Morphogenetic Protein Receptors; D003042:Cocaine
keywords: bone morphogenetic protein receptor; drug abuse; human immunodeficiency virus-1; pulmonary hypertension; smooth muscle
references.citation: J Clin Invest. 1997 Dec 1;100(11):2824-32
references.pmid: 9389748
references.citation: J Neuroimmune Pharmacol. 2008 Mar;3(1):52-6
references.pmid: 18046654
references.citation: Am J Physiol Lung Cell Mol Physiol. 2011 Sep;301(3):L315-26
references.pmid: 21685241
references.citation: Respir Med. 1996 Mar;90(3):171-4
references.pmid: 8736210
references.citation: Semin Respir Crit Care Med. 2009 Aug;30(4):376-85
references.pmid: 19634077
references.citation: Cell Immunol. 1998 Jun 15;186(2):154-60
references.pmid: 9665758
references.citation: AIDS. 2008 Sep;22 Suppl 3:S35-40
references.pmid: 18845920
references.citation: AIDS. 2008 Apr 23;22(7):825-33
references.pmid: 18427200
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9271-6
references.pmid: 11481487
references.citation: Brain Res. 2005 May 31;1045(1-2):57-63
references.pmid: 15910762
references.citation: J Dermatol Sci. 2009 Feb;53(2):112-9
references.pmid: 19004620
references.citation: J Virol. 1993 Jan;67(1):277-87
references.pmid: 8416373
references.citation: Blood. 2000 Aug 15;96(4):1438-42
references.pmid: 10942389
references.citation: Virology. 2004 Mar 30;321(1):111-9
references.pmid: 15033570
references.citation: Am J Pathol. 2007 Sep;171(3):790-9
references.pmid: 17640969
references.citation: AIDS. 2012 Jul 17;26(11):1387-92
references.pmid: 22526521
references.citation: HIV Med. 2008 Aug;9(7):550-6
references.pmid: 18557952
references.citation: Pulm Circ. 2013 Jan;3(1):58-67
references.pmid: 23662175
references.citation: Eur Respir J. 1995 Dec;8(12):2129-38
references.pmid: 8666110
references.citation: J Transl Med. 2010 Apr 16;8:37
references.pmid: 20398386
references.citation: Circ J. 2012;76(6):1501-8
references.pmid: 22374147
references.citation: Nat Med. 1996 Dec;2(12):1371-5
references.pmid: 8946838
references.citation: Bull Soc Pathol Exot. 2002 Mar;95(1):23-6
references.pmid: 12012958
references.citation: J Pathol. 2003 Apr;199(4):509-16
references.pmid: 12635142
references.citation: AIDS Res Hum Retroviruses. 2011 Feb;27(2):103-11
references.pmid: 20961277
references.citation: Lab Invest. 1992 Sep;67(3):338-49
references.pmid: 1405492
references.citation: N Engl J Med. 2003 Feb 6;348(6):500-9
references.pmid: 12571257
references.citation: J Biol Chem. 2010 Nov 26;285(48):37641-9
references.pmid: 20870717
references.citation: Kidney Int. 2003 Jun;63(6):2242-53
references.pmid: 12753314
references.citation: Arterioscler Thromb Vasc Biol. 2013 Nov;33(11):2585-95
references.pmid: 24008158
references.citation: N Engl J Med. 2003 Sep 18;349(12):1113-22
references.pmid: 13679525
references.citation: Respir Res. 2011 Aug 05;12 :103
references.pmid: 21819559
references.citation: Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10142-7
references.pmid: 11504923
references.citation: Adv Exp Med Biol. 2010;661:299-308
references.pmid: 20204738
references.citation: Behav Pharmacol. 1993;4(4):375-387
references.pmid: 11224206
references.citation: Am J Physiol. 1988 Dec;255(6 Pt 2):H1484-91
references.pmid: 3144186
references.citation: Circulation. 2010 May 11;121(18):2045-66
references.pmid: 20458021
references.citation: Am J Pathol. 2008 Apr;172(4):1100-11
references.pmid: 18310503
references.citation: Am J Respir Crit Care Med. 2012 Jun 1;185(11):1235-43
references.pmid: 22447963
references.citation: Am J Respir Crit Care Med. 2006 Aug 15;174(4):437-45
references.pmid: 16728715
references.citation: Am J Respir Cell Mol Biol. 2008 Aug;39(2):218-26
references.pmid: 18314538
references.citation: Pulm Circ. 2013 Dec;3(4):739-56
references.pmid: 25006392
references.citation: Clin Microbiol Rev. 2002 Apr;15(2):310-26
references.pmid: 11932235
references.citation: Hepatology. 2008 Jul;48(1):196-203
references.pmid: 18537192
references.citation: Cell. 1998 Feb 20;92(4):451-62
references.pmid: 9491887
references.citation: Am J Respir Cell Mol Biol. 2011 Jul;45(1):40-52
references.pmid: 20802087
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Mar;290(3):L450-8
references.pmid: 16361357
references.citation: Circulation. 2008 Sep 30;118(14):1486-95
references.pmid: 18824655
references.citation: Alcohol. 1999 Jan;17(1):13-8
references.pmid: 9895032
references.citation: Circulation. 2001 Aug 14;104(7):790-5
references.pmid: 11502704
references.citation: Pharmacol Biochem Behav. 1996 Apr;53(4):911-8
references.pmid: 8801597
references.citation: J Appl Physiol (1985). 1991 Apr;70(4):1861-6
references.pmid: 2055865
references.citation: Circulation. 2010 Jun 29;121(25):2747-54
references.pmid: 20547927