It is evident from the preceding discussion that hs-CRP and other proin-flammatory indices could be used as independent risk factors for cardiovascular diseases and atherothrombosis. High levels of hs-CRP, IL-6, IL-18,
TNF-a, amyloid A, MPO, fibrinogen, and leukocytosis appear to predict future cardiovascular risk in apparently healthy men and women. Despite these findings, the exact mechanism(s) involved in cardiovascular disease process remains unclear. It is likely that markers such as CRP and MPO are closely linked to the underlying pathophysiology, that is, low-grade systemic inflammation. High hs-CRP concentration may thus simply reflect the underlying inflammatory process ultimately responsible for the initiation and progression of atherosclerosis that finally results in CHD. Since atherosclerosis occurs as a result of failure of the antithrombotic properties of endothelium, it is possible that increased hs-CRP is an indication that endothelial cells are no longer able to perform their antithrombotic actions adequately. In other words, increased hs-CRP concentration and other proinflammatory markers provide an indication that endothelial cells have failed to produce antithrombotic molecules (NO and PGI2) and that inflammation is likely responsible.
This premise is supported by the observations that CRP induced matrix metalloproteinase-1 (MMP-1) expression through the Fc region of the IgG with cell surface receptor II (Fc gamma RII) and extracellular signal-related kinase pathway, upregulated IL-8 in human aortic endothelial cells via NF-k B, promoted MCP-1-mediated chemotaxis by upregulating CC-chemokine receptor 2 expression in monocytes, and attenuated endothelial progenitor cell survival, differentiation, and function via inhibiting NO generation . These events initiate and perpetuate inflammation and atherosclerosis and induce atherosclerotic plaque instability. Studies using human CRP trans-genic animal models showed that CRP promoted atherothrombosis and increased plasminogen activator inihibitor-1. There is substantial evidence to suggest that CRP is not only produced by liver but also by endothelial cells indicating that localized production of CRP could be responsible for atherosclerotic lesions. CRP binds to Fc gamma receptors on leukocytes. It significantly upregulated surface expression of Fc gamma receptors, CD32, as well as CD64 on human aortic endothelial cells and colocalized with CD32 and CD64. The increase in IL-8, ICAM-1, and VCAM-1, and decrease in eNO and PGI2 induced by CRP was abrogated by specific antibodies to CD32 and CD64. These results suggest that the biological effects of CRP are mediated via binding and internalization through Fc gamma receptors, CD32, and CD64 . CRP selectively enhanced intracellular generation of ROS in monocytes and neutrophils , decreased PGI2 release from human aortic endothelial cells by inactivating PGIS (PGI2 synthase) via nitration , and also directly inhibited NO generation by cytokine-stimulated vascular smooth muscle cells , and most importantly, induced apoptosis in human coronary vascular smooth muscle cells . All these actions of
Liver, Endothelial cells
Fc gamma receptors, CD32, CD64 on leukocytes and endothelial cells
Fig. 3. Actions of CRP that is relevant to its role in atherosclerosis and as a predictor of future development of CHD and metabolic syndrome X and their prognosis.
CRP ultimately lead to the development and progression of atherosclerosis and CHD (Fig. 3).
Despite these findings, the role of CRP in atherosclerosis is not without controversy. Taylor et al.  reported that CRP-induced in vitro endothelial cell activation was an artifact caused by azide and LPS present in many CRP preparations. It was reported that cCRP (Escherichia coli-derived CRP) but not in-house-generated azide-free recombinant and ascites-purified CRP were responsible for changes in cell proliferation, morphology, apoptosis, and expression of eNO synthase and ICAM-1, MCP-1, IL-8, von Willebrand factor secretion by endothelial cells . It was observed that this ability of cCRP to induce activation of endothelial cells was lost on extensive dialysis, suggesting that low-molecular weight contaminants were responsible. Indeed, the effects of cCRP were mirrored by the presence of azide or LPS thus indicating that contaminated cCRP commercial preparations were likely responsible for the endothelial activation events reported in this study. These results led to the conclusion that CRP, per se, does not activate endothelial cells. This finding, however, does not mean that there is no relationship between the elevated plasma CRP levels and their correlation with prediction and prognosis of cardiovascular events. This finding suggests that CRP may not be solely responsible for all biological events associated with atherosclerosis, it may only be a marker of events that are occurring.
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