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.

Low apoA-I is associated with insulin resistance in patients with impaired glucose tolerance: a cross-sectional study

“…Hyperinsulinemia caused by insulin resistance directly stimulates the in vitro migration of neutrophils and monocytes in response to chemokines that are secreted by atherosclerotic plaques [27]. Hyperinsulinemia might promote atherosclerotic plaque necrosis by accelerating macrophage death [28]. In particular, hyperinsulinemia induces the production of matrix metalloproteinase-9 (MMP-9), which provokes plaque instability and rupture [29].…”

Insulin Resistance: A Proinflammatory State Mediated by Lipid‐Induced Signaling Dysfunction and Involved in Atherosclerotic Plaque Instability

“…In particular, insulin directly increases neutrophil and monocyte in vitro migration in response to chemokines secreted in atherosclerotic plaques [129, 130]. Insulin could also favor atherosclerotic plaque necrosis by accelerating macrophage death [131]. Furthermore, insulin induces in vivo production of matrix metalloproteinase-9 (MMP-9), which is responsible for plaque instability and rupture [132–134].…”

High Uric Acid Activates the ROS-AMPK Pathway, Impairs CD68 Expression and Inhibits OxLDL-Induced Foam-Cell Formation in a Human Monocytic Cell Line, THP-1

“…A recent animal study indicated that elevated serum uric acid level exacerbates left ventricular diastolic dysfunction in mice fed a Western diet, which also leads to other pathophysiological processes, including myocardial hypertrophy, oxidative stress, interstitial fibrosis and macrophage proinflammatory polarization [14,15]. Monocytes/ macrophages have critical importance in the development of metabolic syndrome, including gout, obesity-related diseases, insulin resistance and atherosclerosis [12,[16][17][18][19]. However, the relationship between high uric acid (HUA) level and monocyte/macrophage activity remains unclear.…”