An about-face for C-reactive protein?

Human C-reactive protein (CRP) is a liversynthesized blood constituent, the production of which increases rapidly and robustly in parallel with tissue damage, infection, and trauma (1 ). Owing to this predictable behavior, increases in the blood concentration of CRP have long been used as a clinical gauge of inflammation (2 ). More recently, with the introduction of higher-sensitivity laboratory assays, it has become apparent that even a modestly increased baseline CRP concentration in healthy individuals correlates tightly with their increased future risk of cardiovascular disease (3, 4 ). More than 20 prospective epidemiologic studies carried out in populations of individuals with no prior history of cardiovascular disease have demonstrated that a single CRP measurement at baseline is a strong predictor of future cardiovascular events (4 ). The relationship between an increased baseline CRP concentration and vascular risk is apparent for both men and women and remains consistent in studies from around the world. In most cases, this relationship is independent of traditional risk factors, including age, smoking, high blood pressure, and high cholesterol concentrations (4 ). A high preprocedural baseline CRP value is also associated with an increased occurrence of fatal and nonfatal myocardial infarction after percutaneous coronary interventions (4, 5 ). Notably, the reduction in blood CRP that accompanies statin therapy improves clinical outcomes and decreases the progression of atherosclerotic coronary disease independent of cholesterol lowering, a finding that highlights the possibility of using CRP as a therapeutic target (6 – 8 ). Despite indisputable evidence that CRP is associated with inflammation and the risk of cardiovascular disease, the question of whether CRP contributes to either process remains enigmatic. If CRP does participate in the cardiovascular disease process, how does it do so? The report by Fujita et al. in this issue of Clinical Chemistry (9 ) provides a new clue to help answer these nagging questions, and it all has to do with how the pentraxin form of CRP relates to its function (1 ). CRP is a pentameric protein composed of 5 identical subunits noncovalently bound together in radial symmetry around a central pore (1 ). As far as is known, the function of CRP is intimately related to this unusual structure, because the arrangement produces a disk-shaped complex with 2 opposing faces. The ligand-recognition face (the B face) contains the sites that enable binding of phosphocholine (the first CRP ligand identified) when Ca is available (1, 10 ). Other CRP ligands relevant to cardiovascular disease— such as nuclear autoantigens, apoptotic cells, and lipoproteins— have also been identified (1 ), but binding to most of these ligands also requires Ca and can be inhibited by phosphocholine, indicating that the single promiscuous ligand-binding site on the B face can accommodate diverse structural groups. Because each CRP subunit has a binding site, the B face of CRP associates with high avidity to surfaces that display appropriately arranged ligands, such as phosphatidylcholine on the exterior of oxidized LDL and on the surface of apoptotic cells. On the other face of CRP (the A face), the 5 protomers cooperatively form a single larger binding site that can accommodate both complement protein C1q (1, 11 ) and various Fc receptors (1, 12 ). Thus, by triggering activation of the complement system, CRP is able to opsonize targets (1 ). In addition, there is evidence that CRP is present in atherosclerotic lesions alongside complement proteins, and animal studies suggest that CRP activates the complement system and aggravates myocardial injury after ischemia– reperfusion in several species (4 ). By engaging Fc receptors, the A face of CRP also can initiate cellsignaling events; indeed, recent animal studies have indicated a requirement for certain Fc receptors in CRP-mediated vascular disease (13 ). There is no evidence that the A face of CRP can bind C1q and an Fc receptor simultaneously, so what is it that controls whether CRP binds C1q or engages an Fc receptor? Here enters LOX-1. LOX-1, lectin-type oxidized LDL receptor 1, was originally identified as a receptor for atherogenic oxidized LDL in vascular endothelial cells (14 ). LOX-1 shares many attributes with CRP. Like CRP, LOX-1 appears to contribute to multiple stages of cardiovascular disease, such as endothelial dysfunction, atherogenesis, myocardial ischemia–reperfusion injury, and 1 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL. * Address correspondence to the author at: University of Alabama at Birmingham, Department of Medicine, 1825 University Blvd., Birmingham, AL 35294. E-mail [email protected]. Received July 14, 2011; accepted July 21, 2011. Previously published online at DOI: 10.1373/clinchem.2011.172296 2 Nonstandard abbreviations: CRP, C-reactive protein; LOX-1, lectin-type oxidized LDL receptor 1. Clinical Chemistry 57:1