Complement activation products C5a and sC5b-9 are associated with low-grade inflammation and endothelial dysfunction, but not with atherosclerosis in a cross-sectional analysis: The CODAM study

Abstract

Low-grade inflammation is involved in endothelial dysfunction, atherosclerosis and cardiovascular disease (CVD) [ [1] Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012; 32: 2045-2051 Crossref PubMed Scopus (1468) Google Scholar ]. The complement system is an ancient inducer of inflammation, which generates various soluble and membrane-bound factors upon activation [ [2] Ricklin D. Hajishengallis G. Yang K. Lambris J.D. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010; 11: 785-797 Crossref PubMed Scopus (2367) Google Scholar ]. Complement C5a and soluble C5b-9 (sC5b-9) are products of the final step of the complement activation cascade (=terminal complement activation). The anaphylatoxin C5a is a soluble mediator, which can activate immune and endothelial cells [ [3] Guo R.F. Ward P.A. Role of C5a in inflammatory responses. Annu Rev Immunol. 2005; 23: 821-852 Crossref PubMed Scopus (717) Google Scholar ]. sC5b-9 is the circulating form of C5b-9, also called membrane-attack complex, which has been shown to affect endothelial cells in vitro [ [4] Bossi F. Fischetti F. Pellis V. et al. Platelet-activating factor and kinin-dependent vascular leakage as a novel functional activity of the soluble terminal complement complex. J Immunol. 2004; 173: 6921-6927 Crossref PubMed Scopus (81) Google Scholar ]. In humans, C5a and sC5b-9 are increased in acute inflammatory situations and in acute cardiovascular events, where they are thought to mediate ischemia–reperfusion injury [ [5] Arumugam T.V. Magnus T. Woodruff T.M. et al. Complement mediators in ischemia–reperfusion injury. Clin Chim Acta. 2006; 374: 33-45 Crossref PubMed Scopus (103) Google Scholar ]. Indeed, in patients with acute or advanced CVD, C5a and sC5b-9 have been associated with adverse cardiovascular outcomes [ 6 Speidl W.S. Exner M. Amighi J. et al. Complement component C5a predicts future cardiovascular events in patients with advanced atherosclerosis. Eur Heart J. 2005; 26: 2294-2299 Crossref PubMed Scopus (110) Google Scholar , 7 Speidl W.S. Katsaros K.M. Kastl S.P. et al. Coronary late lumen loss of drug eluting stents is associated with increased serum levels of the complement components C3a and C5a. Atherosclerosis. 2010; 208: 285-289 Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar , 8 Mellbin L.G. Bjerre M. Thiel S. Hansen T.K. Complement activation and prognosis in patients with type 2 diabetes and myocardial infarction: a report from the DIGAMI 2 trial. Diabetes Care. 2012; 35: 911-917 Crossref PubMed Scopus (47) Google Scholar , 9 Lindberg S. Pedersen S.H. Mogelvang R. et al. Soluble form of membrane attack complex independently predicts mortality and cardiovascular events in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Am Heart J. 2012; 164: 786-792 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar ]. However, it is currently unknown whether C5a and sC5b-9 are also increased in earlier, less advanced stages of the cardiovascular disease process. Therefore, we investigated the associations of plasma C5a and sC5b-9 with systemic low-grade inflammation, endothelial dysfunction, markers of atherosclerosis and with prevalent CVD in a cohort of middle-aged individuals with a moderately increased cardiometabolic risk.