Abstract
Atherosclerosis is the primary cause of coronary heart disease (CHD), ischemic stroke, and peripheral arterial disease. Despite effective lipid-lowering therapies and prevention programs, atherosclerosis is still the leading cause of mortality in the United States. Moreover, the prevalence of CHD in developing countries worldwide is rapidly increasing at a rate expected to overtake those of cancer and diabetes. Prominent risk factors include the hardening of arteries and high levels of cholesterol, which lead to the initiation and progression of atherosclerosis. However, cell death and efferocytosis are critical components of both atherosclerotic plaque progression and regression, yet, few currently available therapies focus on these processes. Thus, understanding the causes of cell death within the atherosclerotic plaque, the consequences of cell death, and the mechanisms of apoptotic cell clearance may enable the development of new therapies to treat cardiovascular disease. Here, we review how endoplasmic reticulum stress and cholesterol metabolism lead to cell death and inflammation, how dying cells affect plaque progression, and how autophagy and the clearance of dead cells ameliorates the inflammatory environment of the plaque. In addition, we review current research aimed at alleviating these processes and specifically targeting therapeutics to the site of the plaque.
Highlights
Cardiovascular disease is the leading cause of morbidity and mortality in the United States and its prevalence is rapidly increasing in developing countries [1]
While these macrophages are initially beneficial by clearing the subendotheium of these lipoproteins, the macrophages eventually become engorged with lipids resulting in dysregulated lipid metabolism and a shift in macrophage phenotype to that of lipid-laden foam cells [7, 10, 11]
Our goal is to analyze several causes of macrophage cell death in the plaque including inflammation, cholesterol metabolism, endoplasmic reticulum (ER) stress, and mechanisms of opposing the inflammatory environment of the plaque and clearing dead cells, namely efferocytosis and autophagy in addition to emerging therapies aimed at these processes
Summary
Cardiovascular disease is the leading cause of morbidity and mortality in the United States and its prevalence is rapidly increasing in developing countries [1]. Eating the Dead to Keep Atherosclerosis at Bay sequestered in the subendothelium where maladaptive inflammatory responses to these oxLDLs result in the recruitment, infiltration, and differentiation of monocytes into phagocytic macrophages [7,8,9,10] While these macrophages are initially beneficial by clearing the subendotheium of these lipoproteins, the macrophages eventually become engorged with lipids resulting in dysregulated lipid metabolism and a shift in macrophage phenotype to that of lipid-laden foam cells [7, 10, 11]. These macrophages ingest the lipids sequestered in the subendothelium becoming engorged and eventually leading to dysregulated lipid metabolism and foam cell formation [7, 10, 11] These foam cells secrete pro-inflammatory cytokines including MCP-1, which recruit additional monocytes and macrophages in a positive feedback mechanism [15, 16]. These macrophage-like VSMCs engulf lipids becoming foam cells and contributing to plaque progression [16] (Figure 1)
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