Methods and models for monitoring UPR-associated macrophage death during advanced atherosclerosis.
During advanced atherosclerosis, chronic activation of the endoplasmic reticulum (ER) stress pathway, otherwise known as the unfolded protein response (UPR), is strongly associated with atherosclerotic plaque destabilization, the precursor to acute myocardial infarction and sudden death. Destabilized or vulnerable plaques are characterized by features that include thinning of a protective collagenous cap at the interface between the plaque and the vascular lumen and expansion of the necrotic core, a lipid-rich graveyard of dead macrophages. The cell biology of advanced plaque progression is complex and includes multiple cellular stressors that combine to promote chronic inflammation and progressive plaque deterioration. Several of these stressors converge at the ER, leading to activation of the UPR in multiple cell types. In macrophages, prolonged UPR activation triggers apoptosis, which when coupled to defective phagocytic clearance of these dying cells, leads to secondary necrosis and expansion of the plaque necrotic core. Though much insight has been gained recently on the role of the UPR in atherosclerosis, future studies are warranted to determine the cell-type specific contributions of ER stress to athero-progression and the therapeutic potential of UPR modulation. For such objectives to be met, reliable and standardized methodology must be utilized and developed. This chapter summarizes our current understanding of ER stress-induced macrophage apoptosis in atheromata and outlines both in vitro and in vivo methodologies to quantify the UPR in the context of experimental murine-advanced atherosclerosis.
Department of Medicine, Division of Molecular Medicine, Columbia University, New York, USA.
Edward B
EB
Thorp
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D050197:Atherosclerosis / Q000473:pathology*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D009336:Necrosis / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000473:pathology / Q000503:physiopathology*; D013312:Stress, Physiological; D056811:Unfolded Protein Response
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