PMID- 9931102 OWN - NLM STAT- MEDLINE DCOM- 19990226 LR - 20190722 IS - 0194-911X (Print) IS - 0194-911X (Linking) VI - 33 IP - 1 Pt 2 DP - 1999 Jan TI - TNF-alpha-induced migration of vascular smooth muscle cells is MAPK dependent. PG - 183-9 AB - -Migration of vascular smooth muscle cells (VSMC) is a key event in neointimal formation and atherosclerosis that may be linked to the accumulation of inflammatory cells and release of chemotactic cytokines. Tumor necrosis factor-alpha (TNF-alpha) induces chemotaxis of inflammatory cells and fibroblasts, but little is known about chemotactic signaling by TNF-alpha in VSMC. The aim of this study was to investigate the role of TNF-alpha in VSMC migration and to elucidate the chemotactic signaling pathways mediating this action. TNF-alpha (50 to 400 U/mL) induced migration of cultured rat aortic VSMC in a dose-dependent manner. Because activation of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK) is known to be required in platelet-derived growth factor-directed and angiotensin II-directed migration of these cells, we used the MAPK-inhibitor PD98059 to determine if chemotactic signaling by TNF-alpha involves the MAPK pathway as well. We found that TNF-alpha-directed migration was substantially inhibited by PD98059. TNF-alpha (100 U/mL) transiently activated MAPK with a maximal induction 10 minutes after stimulation that returned to baseline levels by 2 hours after treatment. Only a single peak of increased MAPK activity was seen. PD98059 also blocked TNF-alpha-stimulated MAPK activation in a concentration-dependent manner, which is consistent with its inhibition of TNF-alpha-directed migration. To identify which TNF-alpha receptor is involved in TNF-alpha-induced MAPK activation, antibodies against the p55 TNF-alpha receptor-1 (TNF-R1) and the p75 TNF-alpha receptor-2 (TNF-R2) were used. VSMC express both receptors, but TNF-alpha-induced MAPK activation was inhibited only by the TNF-R1 antibody. The TNF-R2 antibody had no effect. Thiazolidinediones are known to inhibit TNF-alpha signaling in adipose tissue and attenuate platelet-derived growth factor-directed and angiotensin II-directed migration in VSMC. We therefore investigated the effects of the thiazolidinediones troglitazone (TRO) and rosiglitazone (RSG) on TNF-alpha-induced migration. Both TRO and RSG inhibited migration, but neither attenuated TNF-alpha-induced MAPK activation, indicating that their antimigration activity was exerted downstream of MAPK. These experiments provide the first evidence that early activation of MAPK is a crucial event in TNF-alpha-mediated signal transduction leading to VSMC migration. Moreover, inhibition of TNF-alpha-directed migration by the insulin sensitizers TRO and RSG underscores their potential as vasculoprotective agents. FAU - Goetze, S AU - Goetze S AD - Division of Endocrinology, Diabetes and Hypertension, University of California, Los Angeles, School of Medicine 90095, USA. FAU - Xi, X P AU - Xi XP FAU - Kawano, Y AU - Kawano Y FAU - Kawano, H AU - Kawano H FAU - Fleck, E AU - Fleck E FAU - Hsueh, W A AU - Hsueh WA FAU - Law, R E AU - Law RE LA - eng GR - HL-58328-03/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Hypertension JT - Hypertension (Dallas, Tex. : 1979) JID - 7906255 RN - 0 (Enzyme Inhibitors) RN - 0 (Flavonoids) RN - 0 (Recombinant Proteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) SB - IM MH - Analysis of Variance MH - Animals MH - Aorta, Thoracic/drug effects/enzymology/*physiology MH - Calcium-Calmodulin-Dependent Protein Kinases/*metabolism MH - Cells, Cultured MH - Chemotaxis/drug effects/*physiology MH - Enzyme Activation MH - Enzyme Inhibitors/pharmacology MH - Flavonoids/pharmacology MH - Kinetics MH - Mitogen-Activated Protein Kinase 1 MH - Mitogen-Activated Protein Kinase 3 MH - *Mitogen-Activated Protein Kinases MH - Muscle, Smooth, Vascular/drug effects/enzymology/*physiology MH - Rats MH - Rats, Sprague-Dawley MH - Recombinant Proteins/pharmacology MH - Tumor Necrosis Factor-alpha/*pharmacology/physiology EDAT- 1999/02/04 00:00 MHDA- 1999/02/04 00:01 CRDT- 1999/02/04 00:00 PHST- 1999/02/04 00:00 [pubmed] PHST- 1999/02/04 00:01 [medline] PHST- 1999/02/04 00:00 [entrez] AID - 10.1161/01.hyp.33.1.183 [doi] PST - ppublish SO - Hypertension. 1999 Jan;33(1 Pt 2):183-9. doi: 10.1161/01.hyp.33.1.183.