Published online before print December 18, 2008, doi: 10.1161/ATVBAHA.108.181099
© 2009 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
Despite Antiatherogenic Metabolic Characteristics, SCD1-Deficient Mice Have Increased Inflammation and Atherosclerosis
From the Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics (M.L.E.M., N.B., P.R., M.A.P., M.R.H.), University of British Columbia, and Child & Family Research Institute, Vancouver, BC, Canada; the Division of Biopharmaceutics,Leiden/Amsterdam Center for Drug Research (M.v.E., R.B.H., T.J.C.v.B.), Gorlaeus Laboratories, Leiden University, The Netherlands; James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research (B.W.C.W., B.M.M.), St. Paul’s Hospital, Vancouver, BC, Canada; Institut National de la, Santé et de la Recherche Médicale (A.K., H.H., M.J.C.), U551, Dyslipoproteinemia and Atherosclerosis Research, Unit, Paris, France; Université Pierre et Marie Curie-Paris 6 (A.K., H.H., M.J.C.), UMR S551, Paris, France; Institut Pasteur de Lille, Département d’Athérosclérose (C.F., B.S.), Lille, France; Institut National de la Santé et de la Recherche Médicale (C.F., B.S.), U545, Lille, France; and Université de Lille 2 (C.F., B.S.), Lille, France.
Correspondence to Michael R. Hayden, Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, and Child & Family Research Institute, 980 West 28th Avenue, Vancouver, BC, Canada V5Z 4H4. E-mail mrh{at}cmmt.ubc.ca
Objective— Absence of stearoyl-CoA desaturase-1 (SCD1) in mice reduces plasma triglycerides and provides protection from obesity and insulin resistance, which would be predicted to be associated with reduced susceptibility to atherosclerosis. The aim of this study was to determine the effect of SCD1 deficiency on atherosclerosis.
Methods and Results— Despite an antiatherogenic metabolic profile, SCD1 deficiency increases atherosclerosis in hyperlipidemic low-density lipoprotein receptor (LDLR)-deficient mice challenged with a Western diet. Lesion area at the aortic root is significantly increased in males and females in two models of SCD1 deficiency. Inflammatory changes are evident in the skin of these mice, including increased intercellular adhesion molecule (ICAM)-1 and ulcerative dermatitis. Increases in ICAM-1 and interleukin-6 are also evident in plasma of SCD1-deficient mice. HDL particles demonstrate changes associated with inflammation, including decreased plasma apoA-II and apoA-I and paraoxonase-1 and increased plasma serum amyloid A. Lipopolysaccharide-induced inflammatory response and cholesterol efflux are not altered in SCD1-deficient macrophages. In addition, when SCD1 deficiency is limited to bone marrow–derived cells, lesion size is not altered in LDLR-deficient mice.
Conclusions— These studies reinforce the crucial role of chronic inflammation in promoting atherosclerosis, even in the presence of antiatherogenic biochemical and metabolic characteristics.
Absence of stearoyl-CoA desaturase-1 (SCD1) unexpectedly increases atherosclerosis lesion area at the aortic root in low-density lipoprotein receptor–deficient mice. This is associated with numerous signs of inflammation, including increases in plasma interleukin-6 and soluble intercellular adhesion molecule-1 and proinflammatory changes in HDL particles.
Key Words: atherosclerosis • inflammation • apolipoproteins • lipoproteins • hyperlipoproteinemia
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