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B activation
Departments of 1 Medicine and 2 Pharmacology, Robert C. Byrd Health Sciences Center, West Virginia University School of Medicine, Morgantown 26506-9157; and 3 Louis A. Johnson Veterans Affairs Medical Center, Clarksburg, West Virginia 26301
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-1
(IL-1
) (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-1
, recombinant
HIV-gp120 (1 µg/ml) alone failed to enhance NO production in CM
(0.5 ± 0.4 vs. 0.4 ± 0.5 µmol/1.25 × 105 cells/48 h, gp120 vs. control, respectively;
n = 12, P = not significant). However,
the addition of gp120 to IL-1
significantly enhanced iNOS mRNA
expression (70 ± 1.5 vs. 26 ± 2.4 optical units, IL-1
+ gp120 vs. IL-1
, respectively; n = 3),
iNOS protein synthesis (42 ± 1.4 vs. 18 ± 0.8 optical
units, IL-1
+ gp120 vs. IL-1
, respectively;
n = 3), and NO production (NO2
)
(6.6 ± 0.6 vs. 4.1 ± 0.8 µmol/1.25 × 105 cells/48 h, IL-1
+ gp120 vs. IL-1
,
respectively; n = 12, P
0.5).
HIV-gp120 enhancement of IL-1
-induced NO2
production was blocked by 10 µM of SB-203580 (SB), a selective p38
protein kinase inhibitor (3.6 ± 0.2 vs. 6.6 ± 0.6 µmol/1.25 × 105 cells/48 h, IL-1
+ gp120 + SB vs. IL-1
+ gp120, respectively; n = 12, P
0.5). HIV-gp120-enhanced
p38 protein kinase activity was associated with an increase in
IL-1
-stimulated NF-
B activity (184 ± 12.7 vs. 92 ± 10.7 optical units, IL-1
+ gp120 vs. IL-1
, respectively;
n = 3). None of these effects was seen with another recombinant HIV-1 protein, Tat. Thus HIV-gp120 enhancement of IL-1
-induced NO production is associated with p38-mediated
activation of NF-
B. Direct effects of HIV-gp120 on CM may provide a
previously unrecognized mechanism contributing to HIV cardiomyopathy.
cytokines; heart; cell signaling; human immunodeficiency virus; nitric oxide
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