C-Reactive Protein Activates Complement in Infarcted Human Myocardium

Abstract

Circulating levels of C-reactive protein (CRP) constitute a cardiovascular risk marker. Immunohistochemical studies have revealed co-localization of CRP and activated complement in human infarcted myocardium suggesting CRP to enhance inflammation in ischemic myocardium by inducing local complement activation. The aim was to establish whether CRP activates complement in infarcted human myocardium and to assess the relationship between this activation and the duration of infarction. Myocardial tissue samples from 56 patients that had died from acute myocardial infarction were evaluated. Specimens were taken from infarcted as well as noninfarcted sites of the heart. CRP-mediated complement activation was assessed by immunohistochemistry and by measuring levels of complement, CRP, and CRP-complement complexes, specific markers for CRP-mediated activation, in homogenates of the heart. Infarctions of 12 hours to 5 days had significantly more extensive depositions of complement and CRP and contained significantly more CRP, activated complement, and CRPcomplement complexes than infarctions that were less than 12 hours old. Levels of CRP complexes correlated significantly with CRP and complement con- Circulating levels of the acute phase reactant C-reactive protein (CRP) constitute a cardiovascular risk factor: levels in healthy persons or patients with stable or unstable angina pectoris are associated with an increased incidence of cardiovascular events. [1][2][3] In addition, the course of CRP after acute myocardial infarction (AMI) is associated with the development of complications and with outcome. 4,5 These associations between CRP and cardiovascular events are considered to reflect that CRP, by virtue of its acute phase behavior, is an indirect parameter for the degree of inflammation ensuing in atherosclerotic lesions or in the infarcted myocardium. However, we have shown that CRP localizes in infarcted human myocardium, similarly as has been reported in a rabbit model for AMI. 6,7 This raises the possibility that CRP participates in the inflammatory changes locally ensuing in the infarcted myocardium. As a matter of fact CRP is able to activate complement via the classical pathway, implying that CRP may enhance inflammation by activating complement. 8 -10 Indeed, Griselli and coworkers 11 have demonstrated in a rat model that human CRP enhances myocardial infarct size by activating complement. Immunohistochemical co-localization of CRP and activated complement in myocardial tissue of patients with AMI suggests a similar proinflammatory role for CRP in human myocardial infarction.7 However, co-localization of CRP and activated complement does not definitely prove that CRP indeed activates complement locally in infarcted myocardium.In the present study we sought for evidence that CRP activates complement in human myocardial infarction, and determined the relationship between such activation and the duration of infarction. Myocardial tissue specimens were obtained from patients who had died from AMI. These specime...

Activated human PMN synthesize and release a strongly fucosylated glycoform of α1-acid glycoprotein, which is transiently deposited in human myocardial infarction

“…In a recent study in which all patients of the present study were included, we found that reperfusion therapy indeed induces larger areas of complement positiveness compared with nonreperfused hearts [40]. However, also in these reperfused hearts, the center of the infarc-tion area showed less-complement depositions similarly, as in the hearts of patients with infarctions not treated with reperfusion therapy.…”

“…Furthermore, in none of the patients was an obstructive thrombus found after 1-3 days infarction, which makes it hard to believe that no reperfusion would have taken place in the infarcted area of patients who did not receive reperfusion therapy. Next to this, we and others have shown that in these infarcted areas also, complement is produced locally by endothelium, which makes it very likely that a source of complement in infarcted areas is also present, even in less-perfused areas [26,40,41].…”

Micronutrient Vitamin Deficiencies and Cardiovascular Disease Risk: Advancing Current Understanding

“…CRP has been shown to worsen pre-existing tissue damage in a complement-dependent pattern [64]. This is in line with a study demonstrating that CRP enhances inflammation in ischemic myocardium by inducing local complement activation [65]; similar results were obtained by several other investigators [66,67,68]. In view of the obvious lack of evidence for benefit, supplementary use of β-carotene or vitamin A for primary prevention of CVD in healthy adults without special nutritional deficiency is not recommended.…”

The Role of Complement in the Pathogenesis of Artery Aneurysms

“…These facts clearly indicate that aneurysm has a different pathogenesis and consequences for aortic walls vs. atherosclerosis. Although increasing emerging evidence obtained from clinical and experimental studies indicates that complement system plays a critical pathogenic role in the development of atherosclerosis Halas et al, 2005;Hansson et al, 1984;Lewis et al, 2009;Meuwissen et al, 2006;Niculescu et al, 1999b;Nijmeijer et al, 2003;Ross, 1999;Seifert and Kazatchkine, 1988;Vlaicu et al, 1985;Wu et al, 2009;Yun et al, 2008), the role of complement system in the pathogenesis of aneurysm remains unclear.…”