Complement activation: an emerging player in the pathogenesis of cardiovascular disease

Abstract

A wealth of evidence indicates a fundamental role for inflammation in the pathogenesis of cardiovascular disease (CVD), contributing to the development and progression of atherosclerotic lesion formation, plaque rupture, and thrombosis. An increasing body of evidence supports a functional role for complement activation in the pathogenesis of CVD through pleiotropic effects on endothelial and haematopoietic cell function and haemostasis. Prospective and case control studies have reported strong relationships between several complement components and cardiovascular outcomes, and in vitro studies and animal models support a functional effect. Complement activation, in particular, generation of C5a and C5b-9, influences many processes involved in the development and progression of atherosclerosis, including promotion of endothelial cell activation, leukocyte infiltration into the extracellular matrix, stimulation of cytokine release from vascular smooth muscle cells, and promotion of plaque rupture. Complement activation also influences thrombosis, involving components of the mannose-binding lectin pathway, and C5b-9 in particular, through activation of platelets, promotion of fibrin formation, and impairment of fibrinolysis. The participation of the complement system in inflammation and thrombosis is consistent with the physiological role of the complement system as a rapid effector system conferring protection following vessel injury. However, in the context of CVD, these same processes contribute to development of atherosclerosis, plaque rupture, and thrombosis.

Figure 1

The 3 pathways of complement activation: classical, mannose-binding lectin (MBL), and alternative, which converge at formation of the C3 convertase complexes, C4b2a and C3bBb, which cleave C3, the main effector protein of the complement cascade, to C3a and C3b. C3b acts as an opsonin targeting C3b-bound “foreign” surfaces for phagocytosis. C3b also incorporates into the C3 convertase complexes to form C5 convertase complexes (C4b2a3b, C3bBb3B), which cleave C5 to C5a and C5b, with C5b subsequently participating in formation of the lytic C5b-9 complex. C3a and C5a are anaphylatoxins, promoting chemotaxis and mast cell degranulation.