title: Vascular smooth muscle cell activation by C-reactive protein.
abstract: OBJECTIVE
  C-reactive protein (CRP) is an important cardiovascular risk factor. Although the role of CRP has been implicated in atherogenesis, its direct effects on vascular cells are poorly defined.
  
  
  METHODS
  We investigated the responses to CRP in vascular smooth muscle cells (VSMC).
  
  
  RESULTS
  The present study shows that CRP induces parallel activation of the redox-responsive transcription factors NF-kappa B (NF-kappaB) and AP-1 and increases the activity of the MAP kinases (MAPKs), extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38MAPK, in VSMC. C-reactive protein increased the expression of early response genes, c-fos and c-jun and inflammatory genes, monocyte chemoattractant peptide (MCP-1) and interleukin-6 (IL-6). When VSMC were incubated with CRP, the inducible nitric oxide synthase (iNOS) promoter was activated. CRP alone was a weak inducer of NO production in VSMC as measured by determining nitrite levels, and interferon-gamma alone was totally ineffective, whereas CRP plus interferon-gamma was a powerful stimulus. This synergy for NO production corresponded to the results of iNOS mRNA expression analyzed by Northern blotting. The NF-kappaB activation caused by CRP was inhibited by 15-deoxy-12,14-prostaglandin J2 and the PPARgamma activators, rosiglitazone and pioglitazone. Fluvastatin and cerivastatin also reduced the activation of NF-kappaB by CRP.
  
  
  CONCLUSIONS
  CRP causes NF-kappaB activation which could lead to the induction of MCP-1, IL-6, and iNOS gene expression. CRP also activates the MAPK-->c-Fos/cJun-->AP-1 pathway. Thus, CRP may play a role in atherogenesis by activating VSMC.
authors.affiliation: Department of Endocrinology and Metabolism, Dokkyo University School of Medicine, Mibu, Tochigi, Japan. yhattori@dokkyomed.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hattori
authors.forename: Michiko
authors.initials: M
authors.lastname: Matsumura
authors.forename: Kikuo
authors.initials: K
authors.lastname: Kasai
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002097:C-Reactive Protein / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D007211:Indoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D000077205:Pioglitazone; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D015850:Interleukin-6; D016328:NF-kappa B; D011725:Pyridines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D009569:Nitric Oxide; D000077340:Fluvastatin; D002097:C-Reactive Protein; C086276:cerivastatin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D000077205:Pioglitazone