TGF-βs and TGF-β receptors in atherosclerosis

Based on diverse evidence. in animals and humans, it has been hypothesized that atherosclerosis. and other injury-induced hyperplasias such as restenosis, may result from a failure in endogenous inhibitory systems that normally limit wound repair and induce regression of wound repair cells. A key defect in one of these inhibitory pathways, the TGF-beta system, has been identified and characterized in both animal models and in human lesions and lesion-derived cells. Cells derived from human lesions are resistant to the antiproliferative and apoptotic effects of TGF-beta, while their normal counterparts from the vascular media are potently inhibited and killed. Both cell types increase PAI-1 production, switch actin phenotypes in response to TGF-beta 1, and produce similar levels of TGF-beta activity, Membrane cross-linking of I-125-TGF-beta 1 indicates that normal human SMC express Type I, II and III receptors. The Type II receptor is strikingly decreased in lesion cells, with little change in the Type I or III receptors. RT-PCR confirmed that the Type II TGF-beta 1 receptor mRNA is reduced in lesion cells. Subsequent analysis of human lesion vs normal tissues confirmed that the Type I receptor was consistently present in the lesion: while the Type II receptor was much more variable, and commonly absent in both coronary artery and carotid artery lesions. Transfection of the Type II receptor into lesion cells partially restores the growth inhibitory response to TGF-beta 1, implying that signaling remains intact. A subset of patients, and cells derived from their lesions, exhibit acquired mutations in the Type II receptor that would explain their resistance, though the majority of cells are resistant without obvious mutational defects. Thus. it is currently being tested whether transcriptional defects or abnormalities in receptor processing may explain the low levels of the Type II receptor. Because TGF-beta 1 is overexpressed in fibroproliferative vascular lesions, receptor-negative cells would be allowed to grow in a slow, but uncontrolled fashion, while overproducing extracellular matrix components. (C) 2000 Published by Elsevier Science Ltd. All rights reserved.