Kan H, Xie Z, Finkel M S
Department of Medicine, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown 26506-9157, West Virginia, USA.
Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H3138-43. doi: 10.1152/ajpheart.2000.279.6.H3138.
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.
人类免疫缺陷病毒（HIV）感染与心肌功能障碍的高发性相关，令人惊讶。潜在机制包括HIV的直接作用、细胞因子介导的间接作用或两者的结合。我们之前报道过，单独的白细胞介素-1β（IL-1β）（500 U/ml）可诱导新生大鼠心肌细胞（CM）产生一氧化氮（NO）。HIV-1包膜糖蛋白120（gp120）对CM中诱导型一氧化氮合酶（iNOS）的影响此前尚未见报道。与IL-1β不同，单独的重组HIV-gp120（1微克/毫升）未能增强CM中的NO产生（分别为0.5±0.4与0.4±0.5微摩尔/1.25×10⁵细胞/48小时，gp120与对照组；n = 12，P无显著性差异）。然而，将gp120添加到IL-1β中可显著增强iNOS mRNA表达（分别为70±1.5与26±2.4光单位，IL-1β + gp120与IL-1β；n = 3）、iNOS蛋白合成（分别为42±1.4与18±0.8光单位，IL-1β + gp120与IL-1β；n = 3）以及NO产生（NO₂⁻）（分别为6.6±0.6与4.1±0.8微摩尔/1.25×10⁵细胞/48小时，IL-1β + gp120与IL-1β；n = 12，P≤0.5）。HIV-gp120增强IL-1β诱导的NO₂⁻产生被10微摩尔的SB-203580（SB）阻断，SB是一种选择性p38蛋白激酶抑制剂（分别为3.6±0.2与6.6±0.6微摩尔/1.25×10⁵细胞/48小时，IL-1β + gp120 + SB与IL-1β + gp120；n = 12，P≤0.5）。HIV-gp120增强的p38蛋白激酶活性与IL-1β刺激的NF-κB活性增加相关（分别为184±12.7与92±10.7光单位，IL-1β + gp120与IL-1β；n = 3）。另一种重组HIV-1蛋白Tat未观察到这些效应。因此，HIV-gp120增强IL-1β诱导的NO产生与p38介导的NF-κB激活相关。HIV-gp120对CM的直接作用可能提供了一种先前未被认识的导致HIV心肌病的机制。
