Atherosclerosis and complement: anaphylatoxin C5a as a new risk marker and therapeutic target

Abstract

The complement cascade is activated within atherosclerotic plaques Activation of the complement system is a major aspect of many chronic inflammatory diseases. Thus, it is not surprising that several lines of evidence suggest that the complement system may also be involved in the pathogenesis of athero sclerosis. The complement system consists of several inactive zymogens that, upon activation, assemble with other components and are converted into active proteases or effector compounds. The complement cascade can be divided into the following three sequential steps: initiation of complement activation by the classical, alternative or the lectin pathway; complement amplification by activation of C3 and C5 convertases; and the effector functions of the terminal pathway, consisting of the terminal complement complex (TCC) C5b-9 and the proinflammatory anaphylatoxins C3a and C5a. A major activator of the classical complement pathway within atherosclerotic plaques is C-reactive protein (CRP) whose effects are pronounced after binding to enzymatically modified LDL, oxidized LDL or apoptotic cells. The classical pathway may also be activated by autoantibodies against oxidized LDL and against heat shock proteins. The alternative pathway is activated by enzymatically modified LDL, apoptotic cells and cellular debris, as well as free cholesterol crystals that can be found within the necrotic core of an atherosclerotic lesion. In addition, Chlamydia pneumoniae may contribute to complement activation by the lectin pathway and coagulation factors could directly activate C3 and C5. Normal arterial intima is free from activated complement; however, when fatty streaks are formed in cholesterol-fed rabbits, complement