Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:975-982
Published online before print April 25, 2002, doi: 10.1161/01.ATV.0000019729.39500.2F
Published online before print April 25, 2002, doi: 10.1161/01.ATV.0000019729.39500.2F
© 2002 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Transforming Growth Factor-ß Mediates Balance Between Inflammation and Fibrosis During Plaque Progression
From the Departments of Pathology (E.L., M.G., M.J.A.P.D.) and Immunology (M.S., P.H.), Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, the Netherlands, and Biogen Inc (P.G., V.E.K.), Cambridge, Mass.
Correspondence to M.J.A.P. Daemen, MD, PhD, Department of Pathology, P. Debeyelaan 25, 6202 AZ Maastricht, Netherlands. E-mail MDA{at}LPAT.AZM.NL
Abstract— The transition from stable to rupture-prone and ruptured atherosclerotic plaques involves many processes, including an altered balance between inflammation and fibrosis. An important mediator of both is transforming growth factor (TGF)-ß, and a pivotal role for TGF-ß in atherogenesis has been postulated. Here, we determine the in vivo effects of TGF-ß inhibition on plaque progression and phenotype in atherosclerosis. Recombinant soluble TGF-ß receptor II (TGFßRII:Fc), which inhibits TGF-ß signaling, was injected in apolipoprotein E-deficient mice for 12 weeks (50 µg, twice a week intraperitoneally) as early treatment (treatment age 5 to 17 weeks) and delayed treatment (age 17 to 29 weeks). In the early treatment group, inhibition of TGF-ß signaling treatment resulted in a prominent increase in CD3- and CD45-positive cells in atherosclerotic lesions. Most profound effects were found in the delayed treatment group. Plaque area decreased 37.5% after TGFßRII:Fc treatment. Moreover, plaque morphology changed into an inflammatory phenotype that was low in fibrosis: lipid cores were 64.6% larger, and inflammatory cell content had increased 2.7-fold. The amount of fibrosis decreased 49.6%, and intraplaque hemorrhages and iron and fibrin deposition were observed frequently. TGFßRII:Fc treatment did not result in systemic effects. These results reveal a pivotal role for TGF-ß in the maintenance of the balance between inflammation and fibrosis in atherosclerotic plaques.
Key Words: atherosclerosis • transforming growth factor-&bgr • inflammation • fibrosis
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