Journal
CARDIOVASCULAR RESEARCH
Volume 65, Issue 3, Pages 674-682Publisher
OXFORD UNIV PRESS
DOI: 10.1016/j.cardiores.2004.10.031
Keywords
cytokines; growth factors; receptors; signal transduction; veins
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Funding
- NHLBI NIH HHS [HL 63288, HL 64744] Funding Source: Medline
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Objective: Because tumor necrosis factor-alpha (TNF) has been implicated in the pathogenesis of vein graft neointimal hyperplasia, we sought to determine mechanisms by which TNF could induce proliferative and migratory responses in smooth muscle cells (SMCs). Methods and results: In rabbit jugulocarotid interposition vein grafts, SMCs expressed TNF as early as four days postoperatively. In rabbit aortic SMCs, TNF and platelet-derived growth factor (PDGF) elicited comparable migration (1.7-fold/basal), and their effects were partially additive. In contrast, while TNF failed to promote SMC [H-3]thymidine incorporation alone, it doubled the [H-3]thymidine incorporation observed with PDGF alone. To gain mechanistic insight into these phenomena, we found that TNF and PDGF each activated p38(mapk) equivalently in SMCs, but that PDGF was two to three times more efficacious than TNF in activating SMC extracellular signal-regulated kinases (ERK) 1 and 2 and phosphoinoside 3-kinase. However, only TNF activated NFkappaB. SMC [H-3]thymidine incorporation that depended on TNF, but not PDGF, was abolished by overexpression of a dominant-negative IkappaBalpha mutant. Inhibition of ERK activation by U0126 reduced SMC migration stimulated only by PDGF (by 35%, P<0.05), but not by TNF. Inhibition of phosphoinositide 3-kinase by LY294002, however, significantly reduced both TNF- and PDGF-stimulated chemotaxis (by 38-54%, P<0.05). In contrast, both U0126 and LY294002 abolished SMC [H-3]thymidine incorporation induced by either TNF, PDGF, or both agonists. Conclusions: In primary rabbit SMCs, TNF promotes migration and mitogenesis through signaling mechanisms that are both distinct from and overlapping with those employed by PDGF. TNF-induced SMC mitogenesis requires complementary co-stimulation with other growth factors. European Society of Cardiology. Published by Elsevier B.V.
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