A wealth of evidence indicates a fundamental role for inflammation in

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. of cytokine release from vascular easy 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 usually 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. 1 Introduction Cardiovascular disease (CVD) is usually a leading cause of morbidity and mortality CT19 worldwide. Major modifiable risk factors for cardiovascular disease include smoking physical inactivity poor diet and obesity factors which contribute to a proinflammatory state [1]. Inflammation is usually recognised to SM-130686 play fundamental role in the pathogenesis of CVD contributing to the development and progression of atherosclerotic lesion formation plaque rupture and thrombosis [2]. The role of SM-130686 inflammatory processes is usually highlighted by studies demonstrating that elevated levels of inflammatory markers precede and predict the development of CVD and cardiovascular mortality [3-9]. The most widely studied inflammatory factor is usually C-reactive protein (CRP) which has consistently been shown to predict the development of CVD [10]. Whilst it is widely accepted that CRP is an important biomarker it is also clear that CRP levels can be induced by a wide variety of stimuli including acute and chronic contamination and are elevated in various disease processes associated with inflammation indicating a lack of specificity [11 12 Whether CRP plays a functional role in CVD remains controversial [2 12 although it has clearly been shown to be present in atherosclerotic plaques colocalised with activated complement components [13 14 CRP is usually a member of the pentraxin family of pattern recognition molecules which recognises and binds to “foreign” molecules leading to activation of the classical complement cascade [15]; therefore a potential mechanistic role for CRP in CVD may be mediated via complement activation. This paper provides an overview of the inflammatory processes underpinning development of CVD and the increasing body of evidence supporting a functional role for complement activation in the pathogenesis of CVD through pleiotropic effects on endothelial and haematopoietic cell function and haemostasis. 2 The Complement System 2.1 Activation of the Complement Cascade The complement system plays a SM-130686 fundamental role in innate immunity in addition to enhancing adaptive immune responses and is therefore a primary line of defence against infection following injury [16]. Three different pathways of complement activation are known the classical pathway mannose-binding lectin pathway (MBL) and alternative pathways [17 18 as shown in Physique 1. The classical pathway involves antigen/antibody or CRP/“foreign” molecule complexes interacting with C1 complex components (C1q C1r and C1s) leading to cleavage of C4 and C2 and formation of the classical C3 convertase C4b2a [17]. The MBL pathway involves MBL or ficolin interactions with carbohydrate or glycoprotein moieties on pathogen surfaces and binding of MBL-associated serine proteases (MASP) also leading to cleavage of C4 and C2 and formation of C4b2a [19]. Whilst five MASP proteins are currently known (MASP 1-3 MAp19 MAP1) MASP-2 is required for activation of the MBL pathway with MASP-1 acting to augment SM-130686 the action of MASP-2; the biological relevance of the other MASP proteins is largely unclear [20]. The alternative pathway is usually constitutively active as a result of low-level hydrolysis of the C3 thioester bond-generating C3H2O [21]. Alternative pathway activation involves conversation of C3H2O or C3b (generated by either the classical or MBL pathways) with SM-130686 factor B which is usually cleaved by factor D to generate the alternative C3 convertase C3H2OBb or C3bBb [21]. Properdin enhances alternative cascade activation by stabilising the alternative C3 convertases.