© 1996 American Heart Association, Inc.
Articles |
ßig-h3, a Transforming Growth Factor–ß–Inducible Gene, Is Overexpressed in Atherosclerotic and Restenotic Human Vascular Lesions
From the Departments of Pathology and Medicine (E.R.O'B., M.R.G., T.W.Z., S.M.S.), University of Washington School of Medicine, Seattle; Bristol Myers Squibb (K.L.B., A.P.), Seattle, Washington; Sequoia Hospital (T.H., J.B.S.), Redwood City, Calif; Kokura Memorial Hospital (T.K., M.N.), Kitakyushu, Japan; and the Department of Medicine (H.M.), University of British Columbia, Vancouver, Canada.
Correspondence to Edward R. O'Brien, MD, FRCP(C), Department of Medicine (Cardiology), Vascular Biology Laboratory, University of Ottawa Heart Institute, 1053 Carling Ave, Ottawa, Ontario, Canada K1Y 4E9. E-mail eobrien@ohi-net.heartinst.on.ca.
Abstract Transforming growth factor–ß (TGF-ß) plays an important role in vascular lesion formation and possibly the renarrowing process ("restenosis") that occurs after balloon angioplasty. Secreted in a latent form by most cells, TGF-ß requires enzymatic conversion before it is biologically active. TGF-ß–inducible gene h3 (ßig-h3) is a novel molecule that is induced when cells are treated with TGF-ß1. This study examined the expression of ßig-h3 in normal and diseased human vascular tissue. To determine the expression pattern of ßig-h3 in human arteries, immunocytochemistry was performed on tissue sections from (1) normal internal mammary arteries, (2) the proximal left anterior descending coronary artery (with minimal intimal thickening) of 15 patients aged 18 to 40 years, (3) primary and restenotic coronary lesions from 7 patients, and (4) fresh directional atherectomy tissue from 11 patients. A polyclonal antibody consistently immunodetected ßig-h3 protein in endothelial cells of all vascular tissue. In normal coronary arteries of young individuals, ßig-h3 protein was absent from the intima and media but was found in the subendothelial smooth muscle cells of some arteries with modest intimal thickening. In diseased arteries ßig-h3 protein was more abundant in the intima than the media. Restenotic coronary lesions tended to show higher levels of immunodetectable ßig-h3 protein, especially in areas of dense fibrous connective tissue. ßig-h3 protein was immunodetected in the cytoplasm of plaque macrophages as well as smooth muscle and endothelial cells. By using in situ hybridization on fresh directional atherectomy specimens, we found ßig-h3 mRNA to be overexpressed by plaque macrophages and smooth muscle cells. Nondiseased human internal mammary arteries also expressed ßig-h3 mRNA in endothelial cells but not in the smooth muscle cells of the normal intima and media. These results document the expression of ßig-h3 in diseased human arterial tissue and support the hypothesis that active TGF-ß plays a role in atherogenesis and restenosis.
Key Words: transforming growth factor–ß–inducible gene h3 • transforming growth factor–ß • atherosclerosis • restenosis
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