1

Admission Discharge 3 Months 1 Year

Timing relative to presentation with ACS Fig. 4. Persistent elevation in CRP concentration up to 1 yr after index event. (Modified from ref. 18.)

Admission Discharge 3 Months 1 Year

Timing relative to presentation with ACS Fig. 4. Persistent elevation in CRP concentration up to 1 yr after index event. (Modified from ref. 18.)

Fig. 5. CRP production by the liver is a consequence of intravascular inflammation as well as its promoter. CRP indeed exerts direct effects on endothelium, monocytes (M), and lymphocytes (L).

act either by modulating the inflammatory reaction or by activating the endothelium and the monocyte and, as shown in animal models, by direct procoagulant activity.

Pasceri et al. (47) showed a direct proinflammatory effect of CRP on human umbilical vein and coronary artery cells. Endothelial cells were incubated with recombimant human CRP and the induction of adhesion molecules was assessed by cytofluorimetry. CRP induced expression of adhesion molecules and, intriguingly, this effect was dependent on the presence of human plasma, suggesting the role of some additional inflammatory mediator. CRP also induces production of the chemoattractant monocyte chemoattractant pro-tein-1 (MCP-1), a chemokine involved in monocyte recruitment and activation, by endothelial cells (48). Of interest, simvastatin, but not aspirin, inhibited this action. Liuzzo et al. (49) showed that CRP may induce directly monocyte nuclear factor k-B, a nuclear factor that is a key step for the synthesis of new proinflammatory mediators.

CRP has been suggested to induce the procoagulant tissue factor in monocyte, although this finding has not been confirmed (50). More recently, Devaraj et al. (51) described a direct prothrombotic property of CRP. In their study, CRP induced production of the procoagulant plasminogen activator inhibitor-1 (PAI-1) in endothelial cells. A prothrombotic role of CRP has also been elegantly described in an animal model (52). Human CRP transgenic mice were compared with wild-type (WT) mice after mechanical arterial damage. Only human CRP transgenic mice developed thrombotic occlusion of the damaged artery as compared with WT mice, which have only trace CRP, with different properties than in humans. In addition, Wang et al. (53) demonstrated that CRP may change gene expression in endothelial cells. CRP led to overexpression ofgenes for PAI-1, IL-8, MCP-1, fibronectin-1 and connexin 43, all implicated in thrombosis, inflammation, and atheroscerotic plaque formation.

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