CXCR4 receptor antagonist blocks cardiac myocyte p38 MAP kinase phosphorylation by HIV gp120.
The prognosis for patients with human immunodeficiency virus (HIV) infection has improved remarkably as a result of effective antiretroviral therapy. This has resulted in an increased awareness of cardiac complications from HIV infection, including cardiomyopathy and overt heart failure. Mechanisms responsible for HIV cardiomyopathy and heart failure are unknown, but may include direct effects of HIV proteins on the heart. We have previously reported that the HIV envelope glycoprotein, gp120, has a p38 MAP kinase-dependent negative inotropic effect on adult rat ventricular myocytes (ARVM). This signaling pathway presumably results from the binding of gp120 to a specific receptor on the surface of cardiac myocytes. HIV gp120 has been shown to bind to CD4, CXCR4, and CCR5 receptors on lymphocytes and macrophages. Accordingly, we sought to determine if HIV gp120 regulated its negative inotropic effect through activation of one of these binding sites on cardiac myocytes. AMD3100, a highly selective CXCR4 receptor antagonist, reversed HIV gp120-induced negative inotropic effect on ARVM. AMD3100 also blocked HIV gp120 phosphorylation of both p38 MAP kinase and Troponin I. The binding of gp120 to the CXCR4 receptor on ARVM was confirmed by co-immunoprecipitation. We conclude that the negative inotropic effect of HIV gp120 is mediated by a novel signaling pathway that begins with binding to a cardiac myocyte CXCR4 receptor, followed by phosphorylation of both p38 MAP kinase and Troponin I.
Department of Medicine, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, Morgantown, WV, USA.
Youxi
Y
Yuan
Hong
H
Kan
Qiujuan
Q
Fang
Fangping
F
Chen
Mitchell S
MS
Finkel
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001596:Benzylamines; D000080027:Cyclams; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D010477:Perfusion; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D019210:Troponin I / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D019380:Anti-HIV Agents; D001596:Benzylamines; C486264:Cxcr4 protein, rat; D000080027:Cyclams; D015699:HIV Envelope Protein gp120; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D019210:Troponin I; D048051:p38 Mitogen-Activated Protein Kinases; C088327:plerixafor