ABSTRACT

A number of cellular events in the inflammatory advanced atherosclerotic milieu conspire to form the characteristic vulnerable plaque that is strongly associated with acute myocardial infarction and sudden death. A key component of plaque vulnerability is expansion of the lipid necrotic core, which also contains remnants of dead or dying macrophages (Ball et al., 1995). This focal concentration of inflammation, cell death, and tissue destabilization arises through a combination of advanced lesional macrophage apoptosis and defective clearance of these dead cells, a process called defective efferocytosis (Vandivier et al., 2006). In the case of macrophage

apoptosis, chronic activation of ER stress pathways tip the balance from adaptive pro-survival ER stress signaling to networks that promote cell death. The significance of ER stress in other lesional cell types is less well understood, however the current evidence strongly supports roles for regulation of cell survival in smooth muscle cells and endothelial cells (ECs) (Kedi et al., 2009b; Nakano et al., 2006). Importantly, the consequences of ER stress-mediated apoptosis are tightly linked to efferocytosis. That efferocytosis is defective in human advanced plaque suggests that the combination of ER stressinduced apoptosis and defective efferocytosis create the “perfect storm”, which enables a continuous cycle of cell death, reduced clearance, and chronic inflammation (Tabas, 2010; Schrijvers et al., 2005). The causes of defective efferocytosis in atherosclerosis are not well understood. To date, genetic causation experiments in preclinical animal models implicate a handful of clearance signaling pathways that may malfunction during advanced lesional maturation. In this chapter, we provide an overview of the critical and relevant pathways of ER stress and efferocytosis in advanced atheromata. Furthermore, we discuss new therapeutic strategies designed to target these pathways and promote inflammation resolution and plaque stabilization.