Figure 2.

Proposed model of initiation and progression of atherosclerosis with special emphasis on the role of CRP and the complement system. Under normal circumstances (initiation and reversion, normocholesterolemia, left), native LDL entrapped within the arterial intima and associated with specific types of proteoglycans is enzymatically modified (eLDL), leading to a sequence of events that serve to clear the vessel wall of cholesterol. Binding of CRP to eLDL is the first trigger for complement activation (C), but in this early stage the terminal sequence is spared. The physiological sequence of events is concluded by reverse cholesterol transport. If the capacity of the system is overburdened (initiation and progression, hypercholesterolemia, right), this leads to accumulation of eLDL with subsequent generation of potentially harmful C5b-9 complexes by both the classical and alternative pathway as well as accumulation and oxidation of extracellular LDL particles followed by a wealth of well-documented events like MMP production in surrounding cells and subsequent amplification of enzymatic degradation of LDL. Hydrolysis of the core cholesteryl esters and subsequent cholesterol crystallization mediates formation of the inflammasome directly stimulating NLRP3 leading to increased tissue levels of IL-1 β. FFAs play multifaceted roles through their dual capacity to exert stimulatory and cytotoxic effects on neighboring cells (modified from [18]).