Elsevier

Blood Reviews

Volume 27, Issue 1, January 2013, Pages 23-29
Blood Reviews

REVIEW
C-reactive protein and atherothrombosis: Cause or effect?

https://doi.org/10.1016/j.blre.2012.12.001Get rights and content

Abstract

The complex relationship between the inflammatory response and vascular injury and repair is of major importance to the pathogenesis of cardiovascular disease. CRP is not only a strong marker for cardiovascular morbidity but a modulator that suppresses local and systemic thromboregulatory pathways. In the present review we address the question of whether CRP is involved in atherogenesis, in thrombosis, or in both components of the atherothrombotic process. While CRP is present in the atherosclerotic lesion, it is probably not pro-atherogenic and correlates only minimally with atherogenesis. Alas, CRP promotes thrombus formation and vascular occlusion. Thus, CRP is most likely not affecting atheroma build-up but rather the deleterious process of plaque vulnerability and thrombus formation. Dwelling into CRP mechanism of action may lead to the design of new diagnostic modalities that will add to the predictive value of CRP in identifying those patients at high cardiovascular risk. Furthermore, defining the mechanistic domain is the foundation to the cause–effect detection of possible therapeutic interventions to counter CRP morbid effects.

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

  • Further validation of CRP measurements as an indicator for primary and secondary prevention of cardiovascular disease

  • Determination of appropriate therapy for high CRP patients at risk: specific therapy, anti-thrombotic therapy or lipid lowering therapy

  • 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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