Jcb_201412052 1..10

Correspondence to Ira Tabas: [email protected] Abbreviations used in this paper: apoB, apolipoprotein B; CHOP, C/EB-homologous protein; DAMP, damage-associated molecular pattern; LP, lipoprotein; SMC, smooth muscle cell. Atherosclerotic vascular disease is the underlying cause of myocardial infarction (heart attack), stroke, unstable angina (ischemic heart pain), and sudden cardiac death (Lusis, 2000). Collectively, these diseases account for the leading cause of death in the world, and the incidence is continuing to rise as a result of the international epidemic of obesity and type 2 diabetes, which are potent risk factors for atherosclerosis (Braunwald, 1997; World Health Organization, 2014). The disease is initiated by the subendothelial retention of apolipoprotein B (apoB)–containing lipoproteins (LPs) in focal areas of arteries, particularly regions in which laminar flow is disturbed by bends or branch points in the arteries (Williams and Tabas, 1995). Various modifications of the retained LPs likely mimic pathogenand/or damage-associated molecular patterns (DAMPs) and thereby trigger a low-grade inflammatory response. This response lead to activation of endothelial and vascular smooth muscle cells (SMCs); recruitment of monocytes; and accumulation of cellular, extracellular, and lipid material in the subendothelial space, or intima. The cells include monocytederived macrophages, other inflammatory cells, including T cells, B cells, dendritic cells, and mast cells, and SMCs that take on myofibroblast characteristics. Atherosclerotic lesions most often undergo a partial resolution process characterized by the formation of an overlying scar, or fibrous cap (Libby, 2008; Falk et al., 2013). This fibrous cap provides a “protective” barrier between platelets in the blood stream and prothrombotic material in the plaque. Moreover, outward remodeling of the arterial wall, resulting in preservation of lumenal blood flow, and collateral vessel formation help prevent end organ ischemia. Thus, most atherosclerotic lesions do not cause acute vascular disease (Virmani et al., 2002). However, certain types of atherosclerotic lesions over time develop features that can lead to acute thrombotic vascular disease. The features of these so-called “vulnerable plaques” include a large area of necrosis in the intima, called the necrotic or lipid core, thinning of the fibrous cap, and a heightened inflammatory state. These features can lead to breakdown of the aforementioned fibrous cap barrier and thereby promote acute lumenal thrombosis. If the thrombosis is occlusive, end organ damage occurs. Plaque necrosis results from a combination of defective efferocytosis, or clearance of apoptotic cells, and primary necrosis of these cells (Moore and Tabas, 2011). Fibrous cap thinning is likely caused by both defective collagen synthesis by intimal SMCs and increased degradation by matrix metalloproteinases secreted by inflammatory cells. Activation of innate and adaptive immune pathways contribute to the inflammatory response (Hansson and Hermansson, 2011), and this is likely amplified in advanced lesions by the increased production of DAMPs from necrotic cells. Moreover, there are many features of defective inflammation resolution, which may be caused by defective production and/or action of proresolving mediators, which are lipid Atherosclerosis occurs in the subendothelial space (intima) of medium-sized arteries at regions of disturbed blood flow and is triggered by an interplay between endothelial dysfunction and subendothelial lipoprotein retention. Over time, this process stimulates a nonresolving inflammatory response that can cause intimal destruction, arterial thrombosis, and end-organ ischemia. Recent advances highlight important cell biological atherogenic processes, including mechanotransduction and inflammatory processes in endothelial cells, origins and contributions of lesional macrophages, and origins and phenotypic switching of lesional smooth muscle cells. These advances illustrate how indepth mechanistic knowledge of the cellular pathobiology of atherosclerosis can lead to new ideas for therapy. The cell biology of disease