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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1251.)
© 2009 American Heart Association, Inc.

National Cholesterol Awareness Month

TGF-β1 Limits Plaque Growth, Stabilizes Plaque Structure, and Prevents Aortic Dilation in Apolipoprotein E-Null Mice

Andrew D. Frutkin; Goro Otsuka; April Stempien-Otero; Casilde Sesti; Liang Du; Mia Jaffe; Helén L. Dichek; Caroline J. Pennington; Dylan R. Edwards; Madeline Nieves-Cintrón; Daniel Minter; Michael Preusch; Jie Hong Hu; Julien C. Marie; David A. Dichek

From the Departments of Medicine (A.D.F., G.O., A.S.-O., C.S., L.D., M.J., D.M., J.H.H., D.A.D.), Pediatrics (H.L.D.), Physiology (M.N.-C.), Pathology (M.P.), and Immunology (J.C.M.), University of Washington School of Medicine, Seattle; and the School of Biological Sciences (C.J.P., D.R.E.), University of East Anglia, Norwich, Norfolk, UK. Current affiliation for J.C.M.: Inserm U758, Université Claude Bernard Lyon 1, France.

Correspondence to David A. Dichek, MD, University of Washington, 1959 NE Pacific St, Box 357710, Seattle, WA 98195-7710. E-mail ddichek{at}u.washington.edu

Abstract

Objective— Impairment of transforming growth factor (TGF)-β1 signaling accelerates atherosclerosis in experimental mice. However, it is uncertain whether increased TGF-β1 expression would retard atherosclerosis. The role of TGF-β1 in aneurysm formation is also controversial. We tested whether overexpression of active TGF-β1 in hyperlipidemic mice affects atherogenesis and aortic dilation.

Methods and Results— We generated apolipoprotein E-null mice with transgenes that allow regulated overexpression of active TGF-β1 in their hearts. Compared to littermate controls, these mice had elevated cardiac and plasma TGF-β1, less aortic root atherosclerosis (P0.002), fewer lesions in the thoracic and abdominal aortae (P0.01), less aortic root dilation (P<0.001), and fewer pseudoaneurysms (P=0.02). Mechanistic studies revealed no effect of TGF-β1 overexpression on plasma lipids or cytokines, or on peripheral lymphoid organ cells. However, aortae of TGF-β1-overexpressing mice had fewer T-lymphocytes, more collagen, less lipid, lower expression of inflammatory cytokines and matrix metalloproteinase-13, and higher expression of tissue inhibitor of metalloproteinase-2.

Conclusions— When overexpressed in the heart and plasma, TGF-β1 is an antiatherogenic, vasculoprotective cytokine that limits atherosclerosis and prevents aortic dilation. These actions are associated with significant changes in cellularity, collagen and lipid accumulation, and gene expression in the artery wall.

Overexpression of active transforming growth-β1 (TGF-β1) in the heart and plasma of apolipoprotein E-deficient mice retarded aortic root atherosclerosis and slowed the development of aortic aneurysmal disease. Plasma TGF-β1 is an antiatherogenic and vasculoprotective cytokine that alters cellularity, lipid accumulation, inflammation, and gene expression in the artery wall.

Key Words: aneurysm • atherosclerosis • growth substances • inflammation • plaque