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      Blockade of Smooth Muscle Cell Migration and Proliferation in Baboon Aortic Explants by Interleukin-1β and Tumor Necrosis Factor-α Is Nitric Oxide-Dependent and Nitric Oxide-Independent

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          Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) are found in injured and atherosclerotic vessels and have been shown to influence smooth muscle cell (SMC) function in vitro. We have investigated the effects of IL-1β and TNFα on SMC migration and proliferation in baboon aortic explants, an in vitro model of arterial injury. Because platelet-derived growth factor (PDGF) is also present in the vessel wall, we have studied the interaction of PDGF with the cytokines. IL-1β and TNFα inhibited migration of SMCs and synthesis of DNA by SMCs. Cell death (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells and total DNA) was not altered by the cytokines. The cytokines increased levels of nitrite in the medium and L-nitroarginine partly reversed the inhibitory effects of the cytokines indicating a role for nitric oxide in these inhibitory effects. Treatment with indomethacin partially reversed the inhibition of migration, but not DNA synthesis by IL-1β suggesting cyclooxygenase products play an inhibitory role in migration. PDGF-BB reversed the inhibitory effect of the cytokines on SMC migration, but not mitogenesis, without changing levels of nitrite in the medium. These data show that IL-1β and TNFα decrease primate SMC migration and proliferation in arterial tissue partly through production of NO, and that PDGF antagonizes the effect of the cytokines. IL-1β and TNFα may act directly to limit injury-induced intimal hyperplasia by decreasing SMC migration and proliferation.

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          Most cited references 5

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          Signalling mechanisms in the regulation of vascular cell migration.

           H Abedi,  I Zachary (1995)
          The migration of arterial vascular smooth muscle cells (VSMC) is thought to play a central role in atherogenesis and restenosis. The migration of several other cell types, including monocytes, T-lymphocytes and endothelial cells is also involved in the development of the mature atherosclerotic lesion. Several defined growth factors, cytokines and extracellular matrix components which are released at the sites of lesions have been implicated in the regulation of migration of VSMC and other lesion-associated cells. Platelet-derived growth factor BB-homodimer of PDGF (PDGF-BB) is strongly implicated in neo-intima formation in vivo and is the most potent known chemoattractant for VSMC in vitro. Dynamic interactions between cell surface adhesive receptors (integrins) for ECM components, organisation of the actin cytoskeleton and the turnover of focal adhesions are all key processes in cell locomotion and migration. The signal transduction pathways which mediate the chemotactic effects of PDGF-BB and other migration factors on VSMC are unknown, but several classes of cellular components are implicated including components associated with focal adhesions, small GTP-binding proteins of the rho family, and certain substrates of the PDGF beta-receptor. Tyrosine phosphorylation of the novel focal adhesion-associated protein tyrosine kinase, p125 focal adhesion kinase (p125FAK), is regulated by integrins and by several factors which alter actin cytoskeletal organisation. Recent findings suggest that tyrosine phosphorylation of p125FAK and other focal adhesion-associated proteins may be implicated in the chemotactic response of VSMC to PDGF-BB. The migratory response to PDGF-BB may be dependent on both ligand isoform bio-availability and on receptor-isotype expression as well as on down-stream signalling events. Ultimately, cell migration in vivo will be determined by a complex array of diverse extracellular molecules organised in intercellular paracrine/autocrine networks as well as multiple interacting intracellular signal transduction pathways.
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            Accelerated atherosclerosis in mice lacking tumor necrosis factor receptor p55.

            TNF-alpha (TNF) is produced primarily from macrophages and promotes numerous inflammatory reactions associated with atherosclerosis including the induction of vascular adhesion molecules and the recruitment and proliferation of monocyte/macrophages. There are two receptors known to elicit TNF responses, termed p55 and p75. Since p55 is thought to play the primary role in inflammatory processes, we postulated that the absence of p55 in mice would protect against atherosclerosis. In contrast, C57BL/6 mice lacking p55 had aortic sinus lesion sizes 2.3-fold larger than C57BL/6 wild type mice when fed an atherogenic diet (37,123 +/- 3485 microm2 versus 16, 688 +/- 2887 microm2, respectively, p < 0.0004). Plasma lipid levels were not different between strains. A 3-fold increase in the uptake and degradation of acetylated low density lipoprotein for p55-null as compared with wild type mice was demonstrated in cultured peritoneal macrophages. Immunohistochemical staining for scavenger receptor protein in the aortic sinus was more intense in lesions from the p55-null mice as compared with wild type controls. Our results support the concept that increased scavenger receptor activity contributes to excessive fatty streak formation. We conclude that TNF p55 receptors protect against atherosclerotic lesion development in the mouse.
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              Cytokine-induced expression of nitric oxide synthase results in nitrosylation of heme and nonheme iron proteins in vascular smooth muscle cells.

              Nitric oxide synthase (NOS) catalyzes the synthesis of the biomediator, nitric oxide (NO), from L-arginine. We have analyzed NOS induction and activity in cultured rat vascular smooth muscle cells (SMC), which respond to NO by relaxation and inhibition of mitochondrial respiration. Both interferon-gamma and tumor necrosis factor-alpha induced the expression of NOS mRNA and a combination of the two cytokines had a synergistic effect. An internal oligonucleotide complementary to murine macrophage NOS mRNA hybridized to polymerase chain reaction (PCR) products derived from SMC NOS but not brain NOS. Direct sequencing of the PCR products showed a high degree of homology between inducible NOS from SMC and macrophages. Analysis of NOS-dependent nitrite production demonstrated that the enzyme requires NADPH as a cofactor but not calcium for its activity. Cytokine treatment resulted in the development of electron paramagnetic resonance (EPR) signals characteristic for nitrosyl complexes, indicating nitrosylation of SMC molecules by enzymatically synthesized NO. De novo NOS gene transcription and protein synthesis are required for the cytokine-induced protein nitrosylation since addition of actinomycin D and cycloheximide abolished the cytokine effect. At an early stage of cytokine treatment and when low doses of cytokines were used, the EPR signal was dominated by a triplet hyperfine structure typical for hemenitrosyl complexes. With increasing incubation time and/or cytokine dose, the EPR spectra were gradually converted into a pattern resembling that of nonheme iron(II)-nitrosyl thiol complexes. Thereafter, the EPR signal shape no longer changed while the signal intensity increased quantitatively with NO synthesis, suggesting that considerable amounts of NO synthesized could be trapped in the cells by formation of nitrosyl complexes with intracellular molecules. Together, these results provide direct biochemical evidence for cytokine induction of NO synthesis and protein nitrosylation in SMC. This may represent an important second messenger system for cytokine effects on cellular metabolism in blood vessels.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                October 2000
                02 October 2000
                : 37
                : 5
                : 381-389
                Department of Surgery, University of Washington, Seattle, Wash., USA
                25754 J Vasc Res 2000;37:381–389
                © 2000 S. Karger AG, Basel

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                Page count
                Figures: 6, Tables: 2, References: 72, Pages: 9
                Research Paper


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