Vascular smooth muscle cell activation by C-reactive protein.

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.