title: Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E-Deficient Mice.
abstract: We have previously shown that systemic infusion of insulin-like growth factor-1 (IGF-1) exerts anti-inflammatory and antioxidant effects and reduces atherosclerotic burden in apolipoprotein E (Apoe)-deficient mice. Monocytes/macrophages express high levels of IGF-1 receptor (IGF1R) and play a pivotal role in atherogenesis, but the potential effects of IGF-1 on their function are unknown.
  
  
  
  To determine mechanisms whereby IGF-1 reduces atherosclerosis and to explore the potential involvement of monocytes/macrophages, we created monocyte/macrophage-specific IGF1R knockout (MΦ-IGF1R-KO) mice on an Apoe(-/-) background. We assessed atherosclerotic burden, plaque features of stability, and monocyte recruitment to atherosclerotic lesions. Phenotypic changes of IGF1R-deficient macrophages were investigated in culture. MΦ-IGF1R-KO significantly increased atherosclerotic lesion formation, as assessed by Oil Red O staining of en face aortas and aortic root cross-sections, and changed plaque composition to a less stable phenotype, characterized by increased macrophage and decreased α-smooth muscle actin-positive cell population, fibrous cap thinning, and decreased collagen content. Brachiocephalic artery lesions of MΦ-IGF1R-KO mice had histological features implying plaque vulnerability. Macrophages isolated from MΦ-IGF1R-KO mice showed enhanced proinflammatory responses on stimulation by interferon-γ and oxidized low-density lipoprotein and elevated antioxidant gene expression levels. Moreover, IGF1R-deficient macrophages had decreased expression of ABCA1 and ABCG1 and reduced lipid efflux.
  
  
  
  Our data indicate that macrophage IGF1R signaling suppresses macrophage and foam cell accumulation in lesions and reduces plaque vulnerability, providing a novel mechanism whereby IGF-1 exerts antiatherogenic effects.
authors.affiliation: From Departments of Medicine (Y.H., S.S., S.D., P.S., Z.L., P.D.) and Medical Pharmacology and Physiology (Y.H., S.S., M.W., D.W., H.Y., R.K.), University of Missouri School of Medicine, Columbia; and Department of Medicine, Tulane University School of Medicine, New Orleans, LA (S.-Y.S., R.T., P.L.-R.). higashiy@health.missouri.edu.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Higashi
authors.affiliation: From Departments of Medicine (Y.H., S.S., S.D., P.S., Z.L., P.D.) and Medical Pharmacology and Physiology (Y.H., S.S., M.W., D.W., H.Y., R.K.), University of Missouri School of Medicine, Columbia; and Department of Medicine, Tulane University School of Medicine, New Orleans, LA (S.-Y.S., R.T., P.L.-R.).
authors.forename: Sergiy
authors.initials: S
authors.lastname: Sukhanov
authors.affiliation: From Departments of Medicine (Y.H., S.S., S.D., P.S., Z.L., P.D.) and Medical Pharmacology and Physiology (Y.H., S.S., M.W., D.W., H.Y., R.K.), University of Missouri School of Medicine, Columbia; and Department of Medicine, Tulane University School of Medicine, New Orleans, LA (S.-Y.S., R.T., P.L.-R.).
authors.forename: Shaw-Yung
authors.initials: SY
authors.lastname: Shai
authors.affiliation: From Departments of Medicine (Y.H., S.S., S.D., P.S., Z.L., P.D.) and Medical Pharmacology and Physiology (Y.H., S.S., M.W., D.W., H.Y., R.K.), University of Missouri School of Medicine, Columbia; and Department of Medicine, Tulane University School of Medicine, New Orleans, LA (S.-Y.S., R.T., P.L.-R.).
authors.forename: Svitlana
authors.initials: S
authors.lastname: Danchuk
authors.affiliation: From Departments of Medicine (Y.H., S.S., S.D., P.S., Z.L., P.D.) and Medical Pharmacology and Physiology (Y.H., S.S., M.W., D.W., H.Y., R.K.), University of Missouri School of Medicine, Columbia; and Department of Medicine, Tulane University School of Medicine, New Orleans, LA (S.-Y.S., R.T., P.L.-R.).
authors.forename: Richard
authors.initials: R
authors.lastname: Tang
authors.affiliation: From Departments of Medicine (Y.H., S.S., S.D., P.S., Z.L., P.D.) and Medical Pharmacology and Physiology (Y.H., S.S., M.W., D.W., H.Y., R.K.), University of Missouri School of Medicine, Columbia; and Department of Medicine, Tulane University School of Medicine, New Orleans, LA (S.-Y.S., R.T., P.L.-R.).
authors.forename: Patricia
authors.initials: P
authors.lastname: Snarski
authors.affiliation: From Departments of Medicine (Y.H., S.S., S.D., P.S., Z.L., P.D.) and Medical Pharmacology and Physiology (Y.H., S.S., M.W., D.W., H.Y., R.K.), University of Missouri School of Medicine, Columbia; and Department of Medicine, Tulane University School of Medicine, New Orleans, LA (S.-Y.S., R.T., P.L.-R.).
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Li
authors.affiliation: From Departments of Medicine (Y.H., S.S., S.D., P.S., Z.L., P.D.) and Medical Pharmacology and Physiology (Y.H., S.S., M.W., D.W., H.Y., R.K.), University of Missouri School of Medicine, Columbia; and Department of Medicine, Tulane University School of Medicine, New Orleans, LA (S.-Y.S., R.T., P.L.-R.).
authors.forename: Patricia
authors.initials: P
authors.lastname: Lobelle-Rich
authors.affiliation: From Departments of Medicine (Y.H., S.S., S.D., P.S., Z.L., P.D.) and Medical Pharmacology and Physiology (Y.H., S.S., M.W., D.W., H.Y., R.K.), University of Missouri School of Medicine, Columbia; and Department of Medicine, Tulane University School of Medicine, New Orleans, LA (S.-Y.S., R.T., P.L.-R.).
authors.forename: Meifang
authors.initials: M
authors.lastname: Wang
authors.affiliation: From Departments of Medicine (Y.H., S.S., S.D., P.S., Z.L., P.D.) and Medical Pharmacology and Physiology (Y.H., S.S., M.W., D.W., H.Y., R.K.), University of Missouri School of Medicine, Columbia; and Department of Medicine, Tulane University School of Medicine, New Orleans, LA (S.-Y.S., R.T., P.L.-R.).
authors.forename: Derek
authors.initials: D
authors.lastname: Wang
authors.affiliation: From Departments of Medicine (Y.H., S.S., S.D., P.S., Z.L., P.D.) and Medical Pharmacology and Physiology (Y.H., S.S., M.W., D.W., H.Y., R.K.), University of Missouri School of Medicine, Columbia; and Department of Medicine, Tulane University School of Medicine, New Orleans, LA (S.-Y.S., R.T., P.L.-R.).
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: From Departments of Medicine (Y.H., S.S., S.D., P.S., Z.L., P.D.) and Medical Pharmacology and Physiology (Y.H., S.S., M.W., D.W., H.Y., R.K.), University of Missouri School of Medicine, Columbia; and Department of Medicine, Tulane University School of Medicine, New Orleans, LA (S.-Y.S., R.T., P.L.-R.).
authors.forename: Ronald
authors.initials: R
authors.lastname: Korthuis
authors.affiliation: From Departments of Medicine (Y.H., S.S., S.D., P.S., Z.L., P.D.) and Medical Pharmacology and Physiology (Y.H., S.S., M.W., D.W., H.Y., R.K.), University of Missouri School of Medicine, Columbia; and Department of Medicine, Tulane University School of Medicine, New Orleans, LA (S.-Y.S., R.T., P.L.-R.).
authors.forename: Patrice
authors.initials: P
authors.lastname: Delafontaine
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D000066670:Cell Plasticity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D017526:Receptor, IGF Type 1 / Q000172:deficiency* / Q000235:genetics; D012422:Rupture, Spontaneous
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D001057:Apolipoproteins E; D018836:Inflammation Mediators; D007371:Interferon-gamma; D008077:Lipoproteins, LDL; D017526:Receptor, IGF Type 1; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C099252:oxidized low density lipoprotein
keywords: atherosclerosis; inflammation; insulin-like growth factor 1; macrophages