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.