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Cardiovascular Research 2003 58(1):186-195; doi:10.1016/S0008-6363(02)00855-6
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Vascular smooth muscle cell activation by C-reactive protein

Yoshiyuki Hattori*, Michiko Matsumura and Kikuo Kasai

Department of Endocrinology and Metabolism, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan

* Corresponding author. Tel.: +81-282-87-2150; fax: +81-282-86-4632. yhattori{at}dokkyomed.ac.jp

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-{kappa}B) 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-{kappa}B activation caused by CRP was inhibited by 15-deoxy-12,14-prostaglandin J2 and the PPAR{gamma} activators, rosiglitazone and pioglitazone. Fluvastatin and cerivastatin also reduced the activation of NF-{kappa}B by CRP. Conclusions: CRP causes NF-{kappa}B 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.

KEYWORDS Gene expression; Infection/inflammation; Nitric oxide; Signal transduction; Smooth muscle


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