title: HIV gp120 enhances NO production by cardiac myocytes through p38 MAP kinase-mediated NF-kappaB activation.
abstract: Human immunodeficiency virus (HIV) infection is associated with a surprisingly high frequency of myocardial dysfunction. Potential mechanisms include direct effects of HIV, indirect effects mediated by cytokines, or a combination. We have previously reported that interleukin-1beta (IL-1beta) (500 U/ml) alone induced nitric oxide (NO) production by neonatal rat cardiac myocytes (CM). Effects of the HIV-1 envelope, glycoprotein120 (gp120), on inducible NO synthase (iNOS) in CM have not been previously reported. Unlike IL-1beta, recombinant HIV-gp120 (1 microgram/ml) alone failed to enhance NO production in CM (0.5 +/- 0.4 vs. 0.4 +/- 0.5 micromol/1.25 x 10(5) cells/48 h, gp120 vs. control, respectively; n = 12, P = not significant). However, the addition of gp120 to IL-1beta significantly enhanced iNOS mRNA expression (70 +/- 1.5 vs. 26 +/- 2.4 optical units, IL-1beta + gp120 vs. IL-1beta, respectively; n = 3), iNOS protein synthesis (42 +/- 1.4 vs. 18 +/- 0.8 optical units, IL-1beta + gp120 vs. IL-1beta, respectively; n = 3), and NO production (NO(2)(-)) (6.6 +/- 0.6 vs. 4.1 +/- 0.8 micromol/1.25 x 10(5) cells/48 h, IL-1beta + gp120 vs. IL-1beta, respectively; n = 12, P </= 0.5). HIV-gp120 enhancement of IL-1beta-induced NO(2)(-) production was blocked by 10 microM of SB-203580 (SB), a selective p38 protein kinase inhibitor (3.6 +/- 0.2 vs. 6.6 +/- 0.6 micromol/1. 25 x 10(5) cells/48 h, IL-1beta + gp120 + SB vs. IL-1beta + gp120, respectively; n = 12, P </= 0.5). HIV-gp120-enhanced p38 protein kinase activity was associated with an increase in IL-1beta-stimulated NF-kappaB activity (184 +/- 12.7 vs. 92 +/- 10.7 optical units, IL-1beta + gp120 vs. IL-1beta, respectively; n = 3). None of these effects was seen with another recombinant HIV-1 protein, Tat. Thus HIV-gp120 enhancement of IL-1beta-induced NO production is associated with p38-mediated activation of NF-kappaB. Direct effects of HIV-gp120 on CM may provide a previously unrecognized mechanism contributing to HIV cardiomyopathy.
authors.affiliation: Department of Medicine, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown 26506-9157, West Virginia, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kan
authors.forename: Z
authors.initials: Z
authors.lastname: Xie
authors.forename: M S
authors.initials: MS
authors.lastname: Finkel
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D015658:HIV Infections / Q000378:metabolism; D015497:HIV-1; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D007093:Imidazoles; D007375:Interleukin-1; D016328:NF-kappa B; D011725:Pyridines; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580