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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2187.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Molecular Mechanisms of Atherosclerosis in Metabolic Syndrome

Role of Reduced IRS2-Dependent Signaling

Herminia González-Navarro; Ángela Vinué; Marian Vila-Caballer; Ana Fortuño; Oscar Beloqui; Guillermo Zalba; Deborah Burks; Javier Díez; Vicente Andrés

From the Laboratory of Vascular Biology (H.G.-N., A.V., M.V.-C., V.A.), Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia, CSIC, Spain; the Division of Cardiovascular Sciences (A.F., O.B., G.Z., J.D.), Centre for Applied Medical Research; Department of Cardiology and Cardiovascular Surgery, University Clinic (J.D.), School of Medicine, University of Navarra, Pamplona, Spain; and the Centro de Investigación Príncipe Felipe (D.B.), CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Valencia, Spain.

Correspondence to Vicente Andrés, Instituto de Biomedicina de Valencia, Jaime Roig, 11, Valencia, 46010 Spain. E-mail vandres{at}ibv.csic.es

Objective— The mechanisms underlying accelerated atherosclerosis in metabolic syndrome (MetS) patients remain poorly defined. In the mouse, complete disruption of insulin receptor substrate-2 (Irs2) causes insulin resistance, MetS-like manifestations, and accelerates atherosclerosis. Here, we performed human, mouse, and cell culture studies to gain insight into the contribution of defective Irs2 signaling to MetS-associated alterations.

Methods and Results— In circulating leukocytes from insulin-resistant MetS patients, Irs2 and Akt2 mRNA levels inversely correlate with plasma insulin levels and HOMA index and are reduced compared to insulin-sensitive MetS patients. Notably, a moderate reduction in Irs2 expression in fat-fed apolipoprotein E-null mice lacking one allele of Irs2 (apoE^–/–Irs2^+/–) accelerates atherosclerosis compared to apoE-null controls, without affecting plaque composition. Partial Irs2 inactivation also increases CD36 and SRA scavenger receptor expression and modified LDL uptake in macrophages, diminishes Akt2 and Ras expression in aorta, and enhances expression of the proatherogenic cytokine MCP1 in aorta and primary vascular smooth muscle cells (VSMCs) and macrophages. Inhibition of AKT or ERK1/2, a downstream target of RAS, upregulates Mcp1 in VSMCs.

Conclusions— Enhanced levels of MCP1 resulting from reduced IRS2 expression and accompanying defects in AKT2 and Ras/ERK1/2 signaling pathways may contribute to accelerated atherosclerosis in MetS states.

Here we investigated the role of IRS2-dependent signaling in MetS states by analyzing leukocytes from MetS patients, apoE-null mice with partial inactivation of Irs2, and cultured cells. Our results suggest that MCP1 upregulation resulting from reduced IRS2 expression and accompanying defects in AKT2 and Ras/ERK1/2 signaling may contribute to MetS-induced atherosclerosis.

Key Words: insulin resistance/metabolic syndrome • atherosclerosis • IRS2 • AKT • extracellular signal-regulated kinase (ERK)