βig-h3, a Transforming Growth Factor–β–Inducible Gene, Is Overexpressed in Atherosclerotic and Restenotic Human Vascular Lesions

Abstract

Abstract Transforming growth factor–β (TGF-β) 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-β requires enzymatic conversion before it is biologically active. TGF-β–inducible gene h3 (βig-h3) is a novel molecule that is induced when cells are treated with TGF-β1. This study examined the expression of βig-h3 in normal and diseased human vascular tissue. To determine the expression pattern of βig-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 βig-h3 protein in endothelial cells of all vascular tissue. In normal coronary arteries of young individuals, βig-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 βig-h3 protein was more abundant in the intima than the media. Restenotic coronary lesions tended to show higher levels of immunodetectable βig-h3 protein, especially in areas of dense fibrous connective tissue. βig-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 βig-h3 mRNA to be overexpressed by plaque macrophages and smooth muscle cells. Nondiseased human internal mammary arteries also expressed βig-h3 mRNA in endothelial cells but not in the smooth muscle cells of the normal intima and media. These results document the expression of βig-h3 in diseased human arterial tissue and support the hypothesis that active TGF-β plays a role in atherogenesis and restenosis.