Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions

Abstract

Insulin resistance in diabetes and metabolic syndrome is thought to increase susceptibility to atherosclerotic cardiovascular disease, but the underlying mechanisms are poorly understood. To evaluate the possibility that decreased insulin signaling in macrophage foam cells might worsen atherosclerosis, Ldlr(-/-) mice were transplanted with insulin receptor Insr(+/+) or Insr(-/-) bone marrow. Western diet-fed Insr(-/-) recipients developed larger, more complex lesions with increased necrotic cores and increased numbers of apoptotic cells. Insr(-/-) macrophages showed diminished Akt phosphorylation and an augmented ER stress response, leading to induction of scavenger receptor A and increased apoptosis when challenged with cholesterol loading or nutrient deprivation. These studies suggest that defective insulin signaling and reduced Akt activity impair the ability of macrophages to deal with ER stress-induced apoptosis within atherosclerotic plaques.

Vitamin D Suppression of Endoplasmic Reticulum Stress Promotes an Antiatherogenic Monocyte/Macrophage Phenotype in Type 2 Diabetic Patients

“…Insulin resistance is known to induce ER stress in monocytes and macrophages (23,24). In this study, we found that diabetic patients demonstrated increased activation of monocyte/macrophage ER stress when compared with controls, regardless of vitamin D status.…”

“…Interestingly, insulin resistance without hyperglycemia similarly up-regulates adhesion molecules and increases adhesion (21,22). Insulin resistance is also a potent inducer of prolonged endoplasmic reticulum (ER) stress in monocytes and macrophages (23,24). The ER is a dynamic membranous organelle that facilitates correct protein modification, folding, and maturation of proteins.…”

Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

“…Advanced plaques also contain molecules or conditions that promote calcium-based ER stress, including atherogenic lipoproteins and peroxynitrite (8,13), and lesional macrophages display multiple markers of UPR activation in vivo (9,10). Moreover, we recently found that the apoptosis pathway described here is enhanced in insulin-resistant macrophages both in vitro and in advanced atherosclerotic lesions, and the advanced lesions of humans with type II diabetes are characterized by increased lesional macrophage death and plaque necrosis (48,49). Thus, PRR-mediated macrophage apoptosis in advanced atherosclerotic lesions may be relevant particularly in the setting of insulin resistance.…”

High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1

“…Macrophage apoptosis can be induced either by loading with free cholesterol or by uptake of oxLDL (16,31,32). We show that HDL at physiologically relevant concentrations has a potent protective role against macrophage apoptosis induced by either method.…”