HIV gp120 enhances NO production by cardiac myocytes through p38 MAP kinase-mediated NF-kappa B activation

Human immunodeficiency virus (HIV) infection is associated with a surprisin gly high frequency of myocardial dysfunction. Potential mechanisms include direct effects of HIV, indirect effects mediated by cytokines, or a combina tion. We have previously reported that interleukin-1 beta (IL-1 beta) (500 U/ml) alone induced nitric oxide (NO) production by neonatal rat cardiac my ocytes (CM). Effects of the HIV-1 envelope, glycoprotein120 (gp120), on ind ucible NO synthase (iNOS) in CM have not been previously reported. Unlike I L-1 beta, recombinant HIV-gp120 (1 mug/ml) alone failed to enhance NO produ ction in CM (0.5 +/- 0.4 vs. 0.4 +/- 0.5 mu mol/1.25 x 10(5) cells/48 h, gp 120 vs. control, respectively; n = 12, P = not significant). However, the a ddition of gp120 to IL-1 beta significantly enhanced iNOS mRNA expression ( 70 +/- 1.5 vs. 26 +/- 2.4 optical units, IL-1 beta + gp120 vs. IL-1 beta, r espectively; n = 3), iNOS protein synthesis (42 +/- 1.4 vs. 18 +/- 0.8 opti cal units, IL-1 beta + gp120 vs. IL-1 beta, respectively; n = 3), and NO pr oduction (NO2-) (6.6 +/- 0.6 vs. 4.1 +/- 0.8 mu mol/1.25 x 10(5) cells/48 h , IL-1 beta +gp120 vs. IL-1 beta, respectively; n = 12, P less than or equa l to 0.5). HIV-gp120 enhancement of IL-1 beta -induced NO2- production was blocked by 10 muM of SB-203580 (SB), a selective p38 protein kinase inhibit or (3.6 +/- 0.2 vs. 6.6 +/- 0.6 mu mol/1.25 x 10(5) cells/48 h, IL-1 beta gp120 + SB vs. IL-1 beta +gp120, respectively; n = 12, P less than or equal to 0.5). HIV-gp120-enhanced p38 protein kinase activity was associated wit h an increase in IL-1 beta -stimulated NF-kappaB activity (184 +/- 12.7 vs. 92 +/- 10.7 optical units, IL-1 beta + gp120 vs. IL-1 beta, respectively; n = 3). None of these effects was seen with another recombinant HIV-1 prote in, Tat. Thus HIV-gp120 enhancement of IL-1 beta -induced NO2- production i s associated with p38-mediated activation of NF-kappaB. Direct effects of H IV-gp120 on CM may provide a previously unrecognized mechanism contributing to HIV cardiomyopathy.