Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions
- 1 April 2006
- journal article
- Published by Elsevier BV in Cell Metabolism
- Vol. 3 (4), 257-266
- https://doi.org/10.1016/j.cmet.2006.02.008
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.Keywords
Funding Information
- American Heart Association (AHA-0425805T)
This publication has 46 references indexed in Scilit:
- Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptorThe Journal of cell biology, 2005
- The survival kinases Akt and Pim as potential pharmacological targetsJCI Insight, 2005
- Morphologic Findings of Coronary Atherosclerotic Plaques in DiabeticsArteriosclerosis, Thrombosis, and Vascular Biology, 2004
- FoxOs at the Crossroads of Cellular Metabolism, Differentiation, and TransformationCell, 2004
- The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophagesNature, 2003
- TRB3: A tribbles Homolog That Inhibits Akt/PKB Activation by Insulin in LiverScience, 2003
- Biochemistry and molecular cell biology of diabetic complicationsNature, 2001
- Insulin-like Growth Factor-I Extends in VitroReplicative Life Span of Skeletal Muscle Satellite Cells by Enhancing G1/S Cell Cycle Progression via the Activation of Phosphatidylinositol 3′-Kinase/Akt Signaling PathwayJournal of Biological Chemistry, 2000
- Insulin resistance and cardiovascular diseaseJCI Insight, 2000
- Evidence that the death of macrophage foam cells contributes to the lipid core of atheromaAtherosclerosis, 1995