REVIEWC-reactive protein and atherothrombosis: Cause or effect?
Introduction
Cardiovascular disease is the major cause of mortality in the world. In addition to its inflammatory presumed role, C-reactive protein (CRP) has received considerable attention as a risk marker for cardiovascular disease. Chronic modest elevations in CRP levels have been associated with a greater likelihood of acute cardiovascular syndromes including: myocardial infarction, sudden cardiac death, stroke, and peripheral vascular disease.[1], [2], [3], [4], [5] CRP is also a marker for the progression of subclinical vascular disease and for hypertension.[6], [7] Accumulating experimental data supports a role for CRP not only as marker or predictor but rather as a mediator for endothelial dysfunction and arterial thrombosis.
Section snippets
CRP and cardiovascular disease
CRP was discovered in 1930 by Tillett and Francis in Oswald Avery's laboratory during studies of patients with Streptococcus pneumoniae infection.8 Sera obtained from these patients during the early, acute phase of the illness were found to contain a protein that could precipitate the “C” polysaccharide derived from the pneumococcal cell wall. CRP is a highly conserved pentameric plasma protein that participates in the systemic response to inflammation. In humans, plasma levels of CRP may rise
CRP and atherothrombosis
CRP may be both a “marker” and a “maker” of atherothrombosis. A key question is whether CRP is involved in atherogenesis, in thrombosis, or in both components of the atherothrombotic process. Human recombinant CRP, at concentrations known to predict vascular disease, elicits a multitude of effects on endothelial biology favoring a pro-inflammatory and pro-atherosclerotic phenotype. CRP interacts with endothelial cells through a variety of mechanisms, which contribute to endothelial dysfunction.
CRP down-regulates nitric oxide production and bio-availability
An important plausible pathway in modulation of CRP pro-thrombotic activity is via down-regulation of nitric oxide (NO) expression. NO is synthesized by the enzyme NO synthase (NOS) and once released by the endothelium, diffuses to the luminal side of the vessel, where it affects platelet and blood element functions, and to the abluminal side of the vessel, where it affects smooth muscle function.64 In platelets, NO inhibits adhesion and aggregation, thereby promoting blood fluidity and
CRP local activity
Most of the circulating CRP is produced in the liver. Earlier perception that CRP is exclusively produced by the liver was recently proven imprecise. CRP production was observed in human aortic endothelial cells,90 in vascular smooth muscle cells,91 in the kidneys,92 neurons93 and arterial plaque tissue.94 CRP is locally expressed in normal arteries and in degenerated venous grafts.95 Serum and carotid plaque CRP levels were found to correlate with intima to media ratio96 and CRP levels in the
Monomeric and pentameric CRP
Some of the inconsistent results regarding CRP atherothrombotic activity may be attributed to CRP existence in two distinct forms, the native pentameric CRP (nCRP) detectable in serum with both pro-and anti-inflammatory effects and the tissue-bound form-modified or monomeric CRP (mCRP), with predominantly pro-inflammatory effects.100 Habersberger et al. investigated the interaction of the inflammatory phospholipid membranes of microparticles with naïve CRP. They found that microparticles can
Summary
The complex relationship between the inflammatory response and cardiovascular disease has been intensively investigated and debated and yet not fully understood. The acute phase reactant CRP is a strong predictor of cardiovascular morbidity, mainly acute vascular events caused by thrombosis. Emerging data indicate that CRP is not just a marker but rather an active mediator that promotes and accelerates vascular thrombosis. CRP is an important mechanistic link between inflammation and
Research agenda
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Further validation of CRP measurements as an indicator for primary and secondary prevention of cardiovascular disease
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Determination of appropriate therapy for high CRP patients at risk: specific therapy, anti-thrombotic therapy or lipid lowering therapy
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Mechanism of therapy: further delineation of CRP induced thrombosis, receptor, signal transduction and additional pathobiological pathways
Conflict of interest statement
None.
Acknowledgments
This work was supported in part by BSF grant 2007240 to HDD and Israel Chief Scientist grant to HDD.
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2020, Journal of CardiologyCitation Excerpt :Despite the fact that the underlying mechanism of their relationship has not been clarified to date, growing evidence is in favor of the view that CRP is not merely a marker but a direct mediator involved in the pathological process. Histocytological experiments noticed that CRP might affect the progression of disease through various pathways such as activating the complement system and platelets, suppressing fibrinolysis, promoting proliferation of smooth muscle cell, microphage polarization, and lipid deposition [27–29]. Meanwhile, some researchers verified its functions in vivo as driving inflammation, platelet aggregation, and thrombosis in transgenic mice and human beings [30,31].
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