C-reactive protein (CRP) is a short pentraxin mainly found as a pentamer in the circulation, or as non-soluble monomers CRP (mCRP) in tissues, exerting different functions. This review is focused on discussing the role of CRP in cardiovascular disease, including recent advances on the implication of CRP and its forms specifically on the pathogenesis of atherothrombosis and angiogenesis. Besides its role in the humoral innate immune response, CRP contributes to cardiovascular disease progression by recognizing and binding multiple intrinsic ligands. mCRP is not present in the healthy vessel wall but it becomes detectable in the early stages of atherogenesis and accumulates during the progression of atherosclerosis. CRP inhibits endothelial nitric oxide production and contributes to plaque instability by increasing endothelial cell adhesion molecules expression, by promoting monocyte recruitment into the atheromatous plaque and by enzymatically binding to modified low-density lipoprotein. CRP also contributes to thrombosis, but depending on its form it elicits different actions. Pentameric CRP has no involvement in thrombogenesis, whereas mCRP induces platelet activation and thrombus growth. In addition, mCRP has apparently contradictory pro-angiogenic and anti-angiogenic effects determining tissue remodeling in the atherosclerotic plaque and in infarcted tissues. Overall, CRP contributes to cardiovascular disease by several mechanisms that deserve an in-depth analysis.

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Objective-We studied the impact of native (natCRP) and modified CRP (mCRP) isoforms on platelet adhesion and thrombus growth under arterial flow. Methods and Results-Blood was perfused over type I collagen at a wall shear rate of 1500 s Ϫ1 , and platelet deposition and thrombus growth were evaluated by confocal microscopy. natCRP and mCRP were either incubated with blood before perfusion experiments or immobilized in the collagen surface and exposed to flowing blood. mCRP significantly increased platelet adhesion and thrombus growth when directly incubated with blood and when immobilized on a collagen surface (PϽ0.05). In contrast, natCRP did not exert any effect. Confocal immunohistochemistry revealed the presence of CRP on the surface of adhered platelets and within the thrombus and showed an upregulation of P-selectin and CD36 in effluent platelets preincubated with mCRP (PϽ0.05). Flow cytometry analysis of agonist-induced platelet activation demonstrated that mCRP, but not natCRP, significantly increased platelet surface P-selectin (PϽ0.05) without modifying CD63 and PAC-1. Conclusions-Our data indicate that whereas serum natCRP may not affect thrombus growth, mCRP displays a prothrombotic phenotype enhancing not only platelet deposition, but also thrombus growth under arterial flow conditions. (Arterioscler Thromb Vasc Biol. 2008;28:2239-2246.)Key Words: C-reactive protein Ⅲ isoforms Ⅲ thrombosis Ⅲ platelets I n recent years, C-reactive protein (CRP), long associated with inflammation, has emerged as a clinical marker of future cardiovascular events among apparently healthy subjects and of worse prognosis in acute coronary patients. [1][2][3] Thrombus formation on rupture of an atherosclerotic plaque is believed to be the responsible event for most of the coronary syndromes, in a process mainly mediated by platelet adhesion, activation, and aggregation. The first response to vascular injury consists of platelet adhesion to the damaged vessel wall or to exposed tissue components, and is mediated by flow-regulated interactions that have a key influence on subsequent thrombus growth, often culminating in lifethreatening complications. 4,5 Long considered merely a bystander in vascular disease, new evidence indicates that CRP may be not only a marker, but also an active player in the development of cardiovascular pathology. 6 The role of CRP as a modulator of inflammation and thrombosis is controversial, because both proinflammatory and antiinflammatory properties have been ascribed to the molecule. 7-9 For instance, CRP inhibits neutrophil activation and adhesion, 9 and blocks platelet aggregation in vitro, 10,11 whereas arterial injury in CRP-transgenic mice is associated with increased thrombosis. 12 Overexpression of the human CRP gene in atherosclerosis-prone mice has also shown contradictory effects on the development of atherosclerosis. 13,14 To explain these apparently contradictory actions, it was proposed that distinct isoforms of CRP were formed during inflammation. The classically studied serum CRP ...