title: The impact of insulin resistance on macrophage death pathways in advanced atherosclerosis.
abstract: Macrophage death in advanced atherosclerosis causes plaque necrosis, which promotes plaque rupture and acute atherothrombotic vascular events. Of interest, plaque necrosis and atherothrombotic disease are markedly increased in diabetes and metabolic syndrome. We discovered a novel 'multi-hit' macrophage apoptosis pathway that appears to be highly relevant to advanced atherosclerosis. The elements of the pathway include: (a) activation of the unfolded protein response (UPR) by cholesterol overloading of the endoplasmic reticulum or by other UPR activators known to exist in atheromata; and (b) pro-apoptotic signalling involving the type A scavenger receptor (SRA). The downstream apoptosis effectors include CHOP (GADD153) for the UPR and JNK for SRA signalling. Remarkably, components of this pathway are enhanced in macrophages with defective insulin signalling, including UPR activation and SRA expression. As a result, insulin-resistant macrophages show increased susceptibility to apoptosis when exposed to UPR activators and SRA ligands. Moreover, the advanced lesions of atherosclerosis-prone mice reconstituted with insulin-resistant macrophages show increased macrophage apoptosis and plaque necrosis. Based on these findings, we propose that one mechanism of increased plaque necrosis and atherothrombotic vascular disease in insulin resistant syndromes is up-regulation of a two-hit signal transduction pathway involved in advanced lesional macrophage death.
authors.affiliation: Department of Medicine, 630 West 168th Street, Columbia University, New York, NY 10032, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
authors.forename: Tracie
authors.initials: T
authors.lastname: Seimon
authors.forename: Jerry
authors.initials: J
authors.lastname: Arellano
authors.forename: Yankun
authors.initials: Y
authors.lastname: Li
authors.forename: Fabien
authors.initials: F
authors.lastname: Forcheron
authors.forename: Dongying
authors.initials: D
authors.lastname: Cui
authors.forename: Seongah
authors.initials: S
authors.lastname: Han
authors.forename: Chien-Ping
authors.initials: CP
authors.lastname: Liang
authors.forename: Alan
authors.initials: A
authors.lastname: Tall
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
mesh_terms: D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008954:Models, Biological; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051117:Scavenger Receptors, Class A