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Am J Physiol Heart Circ Physiol 277: H1641-H1646, 1999;
0363-6135/99 $5.00
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Vol. 277, Issue 4, H1641-H1646, October 1999

RAPID COMMUNICATION
TNF-alpha enhances cardiac myocyte NO production through MAP kinase-mediated NF-kappa B activation

Hong Kan1, Zirong Xie1, and Mitchell S. Finkel1,2,3

Departments of 1 Medicine and 2 Pharmacology, West Virginia University School of Medicine, Robert C. Byrd Health Sciences Center, Morgantown 26506-9157; and 3 Louis A. Johnson Veterans Affairs Medical Center, Clarksburg, West Virginia 26301

We have previously reported that interleukin-1beta (IL-1beta ) alone induced nitric oxide (NO) production by neonatal rat cardiac myocytes (CM). The effects of tumor necrosis factor-alpha (TNF-alpha ) on inducible NO synthase (iNOS) were not characterized. Unlike IL-1beta , TNF-alpha alone failed to enhance NO production in CM. However, the addition of TNF-alpha to IL-1beta significantly enhanced iNOS mRNA expression, iNOS protein synthesis, and NO production (NO-2). TNF-alpha enhancement of IL-1beta -induced NO-2 production was blocked by PD-98059, a selective mitogen-activated protein (MAP) kinase kinase inhibitor, but not calphostin C (Cal C), a protein kinase C inhibitor. TNF-alpha -enhanced MAP kinase activity was associated with an increase in IL-1beta -stimulated NF-kappa B activity. PD-98059, but not Cal C, inhibited both TNF-alpha -enhanced MAP kinase and NF-kappa B activities. Thus TNF-alpha enhancement of IL-1beta -induced NO production is associated with MAP kinase-mediated activation of NF-kappa B.

cytokines; heart; cell signaling; tumor necrosis factor; nitric oxide; mitogen-activated protein kinase


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