An Essential Role for gp130 in Neointima Formation Following Arterial Injury

Interleukin (IL)-6 induced vascular smooth muscle cell (VSMC) motility in a dose-dependent manner. In addition, IL-6 stimulated tyrosine phosphorylation of gp130, resulting in the recruitment and activation of STAT-3. IL-6–induced VSMC motility was found to be dependent on activation of gp130/STAT-3 signaling. IL-6 also induced cyclin D1 expression in a time- and gp130/STAT-3–dependent manner in VSMCs. Suppression of cyclin D1 levels via the use of its small interfering RNA molecules inhibited IL-6–induced VSMC motility. Furthermore, balloon injury induced IL-6 expression both at mRNA and protein levels in rat carotid artery. Balloon injury also caused increased STAT-3 phosphorylation and cyclin D1 expression, leading to smooth muscle cell migration from the media to the intimal region. Blockade of gp130/STAT-3 signaling via adenovirus-mediated expression of dngp130 or dnSTAT-3 attenuated balloon injury–induced STAT-3 phosphorylation and cyclin D1 induction, resulting in reduced smooth muscle cell migration from media to intima and decreased neointima formation. Together, these observations for the first time suggest that IL-6/gp130/STAT-3 signaling plays an important role in vascular wall remodeling particularly in the settings of postangioplasty and thereby in neointima formation.

[1]  Anping Li,et al.  Cyclin D1 Regulates Cellular Migration through the Inhibition of Thrombospondin 1 and ROCK Signaling , 2006, Molecular and Cellular Biology.

[2]  Nagadhara Dronadula,et al.  Novel Role for STAT-5B in the Regulation of Hsp27–FGF-2 Axis Facilitating Thrombin-Induced Vascular Smooth Muscle Cell Growth and Motility , 2006, Circulation research.

[3]  Nagadhara Dronadula,et al.  Involvement of cAMP-response element binding protein-1 in arachidonic acid-induced vascular smooth muscle cell motility Published, JLR Papers in Press, December 28, 2006. , 2006, Journal of Lipid Research.

[4]  I. Fidler,et al.  Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. , 2005, Cancer research.

[5]  Kenichi Matsubara,et al.  Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma , 2005, Oncogene.

[6]  Anping Li,et al.  Cyclin D1 Represses p300 Transactivation through a Cyclin-dependent Kinase-independent Mechanism* , 2005, Journal of Biological Chemistry.

[7]  T. Nheu,et al.  Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-β signaling , 2005, Nature Medicine.

[8]  J. Lecron,et al.  Role of interleukin‐6 in cardiomyocyte/cardiac fibroblast interactions during myocyte hypertrophy and fibroblast proliferation , 2005, Journal of cellular physiology.

[9]  W. Farrar,et al.  Enforced expression of superoxide dismutase 2/manganese superoxide dismutase disrupts autocrine interleukin-6 stimulation in human multiple myeloma cells and enhances dexamethasone-induced apoptosis. , 2005, Cancer research.

[10]  C. Fielding,et al.  IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[11]  A. Roberts,et al.  The threshold of gp130-dependent STAT3 signaling is critical for normal regulation of hematopoiesis. , 2005, Blood.

[12]  Chunxiang Zhang,et al.  Blockade of Nuclear Factor of Activated T Cells Activation Signaling Suppresses Balloon Injury-induced Neointima Formation in a Rat Carotid Artery Model* , 2005, Journal of Biological Chemistry.

[13]  L. Flowers,et al.  A SOCS-1 peptide mimetic inhibits both constitutive and IL-6 induced activation of STAT3 in prostate cancer cells , 2005, Oncogene.

[14]  Nagadhara Dronadula,et al.  STAT-3-dependent Cytosolic Phospholipase A2 Expression Is Required for Thrombin-induced Vascular Smooth Muscle Cell Motility* , 2005, Journal of Biological Chemistry.

[15]  Nagadhara Dronadula,et al.  An Essential Role of the Jak-2/STAT-3/Cytosolic Phospholipase A2 Axis in Platelet-derived Growth Factor BB-induced Vascular Smooth Muscle Cell Motility* , 2004, Journal of Biological Chemistry.

[16]  P. Heinrich,et al.  Inhibition of gp130 Signaling in Breast Cancer Blocks Constitutive Activation of Stat3 and Inhibits in Vivo Malignancy , 2004, Cancer Research.

[17]  Nagadhara Dronadula,et al.  A Novel Role for Nuclear Factor of Activated T Cells in Receptor Tyrosine Kinase and G Protein-coupled Receptor Agonist-induced Vascular Smooth Muscle Cell Motility* , 2004, Journal of Biological Chemistry.

[18]  E. Lakatta,et al.  Rat Aortic MCP-1 and Its Receptor CCR2 Increase With Age and Alter Vascular Smooth Muscle Cell Function , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[19]  N. Jing,et al.  Role of JAK/STAT Pathway in IL-6-Induced Activation of Vascular Smooth Muscle Cells , 2004, American Journal of Nephrology.

[20]  W. Newman,et al.  Smooth muscle cell migration stimulated by interleukin 6 is associated with cytoskeletal reorganization. , 2003, The Journal of surgical research.

[21]  Amanda Y. Chan,et al.  Cyclin D1 governs adhesion and motility of macrophages. , 2003, Molecular biology of the cell.

[22]  G. Rao,et al.  Cytosolic Phospholipase A2 Is an Effector of Jak/STAT Signaling and Is Involved in Platelet-derived Growth Factor BB-induced Growth in Vascular Smooth Muscle Cells* , 2003, The Journal of Biological Chemistry.

[23]  P. Heinrich,et al.  Two Different Epitopes of the Signal Transducer gp130 Sequentially Cooperate on IL-6-Induced Receptor Activation1 , 2000, The Journal of Immunology.

[24]  U. Ikeda,et al.  Interleukin 6 expression in coronary circulation after coronary angioplasty as a risk factor for restenosis , 2000, Heart.

[25]  M. Meuwissen,et al.  Plaque inflammation in restenotic coronary lesions of patients with stable or unstable angina. , 2000, Journal of the American College of Cardiology.

[26]  R. Kitazawa,et al.  Transcriptional Regulation of Rat Cyclin D1 Gene by CpG Methylation Status in Promoter Region* , 1999, The Journal of Biological Chemistry.

[27]  J. Dumont,et al.  Flavopiridol inhibits smooth muscle cell proliferation in vitro and neointimal formation In vivo after carotid injury in the rat. , 1999, Circulation.

[28]  J. Darnell,et al.  Stat3 as an Oncogene , 1999, Cell.

[29]  P. Libby,et al.  Angiotensin induces inflammatory activation of human vascular smooth muscle cells. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[30]  Itaru Matsumura,et al.  Transcriptional regulation of the cyclin D1 promoter by STAT5: its involvement in cytokine‐dependent growth of hematopoietic cells , 1999, The EMBO journal.

[31]  J. Darnell,et al.  Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors , 1995, Science.

[32]  M. Reidy,et al.  Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. , 1994, Circulation research.

[33]  O. Silvennoinen,et al.  Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[34]  C. Schindler,et al.  Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. , 1994, Science.

[35]  L. Ramos,et al.  Inhibition of smooth muscle cell proliferation and DNA synthesis by Vasoprin--a biologic response modifier. , 1993, Atherosclerosis.

[36]  R. Ross,et al.  Role of endogenous platelet-derived growth factor in arterial smooth muscle cell migration after balloon catheter injury. , 1993, Arteriosclerosis and thrombosis : a journal of vascular biology.

[37]  U. Ikeda,et al.  Interleukin 6 stimulates growth of vascular smooth muscle cells in a PDGF-dependent manner. , 1991, The American journal of physiology.

[38]  K. Berkner.  Development of adenovirus vectors for the expression of heterologous genes. , 1988, BioTechniques.

[39]  S. Leahy.  Eight ‘Musts’ for Biotechnology , 1988, Bio/Technology.

[40]  M. Reidy,et al.  Kinetics of cellular proliferation after arterial injury. I. Smooth muscle growth in the absence of endothelium. , 1983, Laboratory investigation; a journal of technical methods and pathology.

[41]  R. D. de Winter,et al.  Eosinophilic infiltration in restenotic tissue following coronary stent implantation. , 2006, Atherosclerosis.

[42]  T. Kishimoto,et al.  Gp130 and the interleukin-6 family of cytokines. , 1997, Annual review of immunology.