Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions.
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.
Department of Medicine, Columbia University, New York, New York 10032, USA. sh2068@columbia.edu
Seongah
S
Han
Chien-Ping
CP
Liang
Tracie
T
DeVries-Seimon
Mollie
M
Ranalletta
Carrie L
CL
Welch
Kadesha
K
Collins-Fletcher
Domenico
D
Accili
Ira
I
Tabas
Alan R
AR
Tall
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology*; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005260:Female; D005487:Foam Cells / Q000473:pathology / Q000502:physiology; D015870:Gene Expression; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000737:chemistry* / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009336:Necrosis; D051058:Oncogene Protein v-akt / Q000502:physiology; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction
D007328:Insulin; D051117:Scavenger Receptors, Class A; D002784:Cholesterol; D011972:Receptor, Insulin; D051058:Oncogene Protein v-akt