(Circulation. 1999;99:2883-2891.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Distinct Patterns of Transforming Growth Factor-ß Isoform and Receptor Expression in Human Atherosclerotic Lesions
Colocalization Implicates TGF-ß in Fibrofatty Lesion Development
From Baker Medical Research Institute and Alfred Hospital, Melbourne, Victoria, Australia, and Cardiology Research Center, Moscow, Russia (A.K., V.S., E.T.).
Correspondence to Dr Alex Bobik, Baker Medical Research Institute, PO Box 6492, Melbourne 8008, Victoria, Australia. E-mail alex.bobik{at}baker.edu.au
Background—Some animal studies suggest that transforming growth factor-ß (TGF-ß) protects vessels from atherosclerosis by preventing intima formation, but others indicate a role in vessel proteoglycan accumulation and lipoprotein retention. To distinguish between these possibilities in humans, immunohistochemical studies were performed examining the coexpression of TGF-ß isoforms and the TGF-ß receptors ALK-5 and TßR-II in aorta during the various stages of atherosclerotic lesion development.
Methods and Results—The spatial relationships between TGF-ß1, TGF-ß3, ALK-5, and TßR-II expression were compared in aortic segments from 21 subjects. Nonatherosclerotic intima contained predominantly TGF-ß1, low concentrations of TßR-II, and barely detectable amounts of ALK-5. In contrast, fatty streaks/fibrofatty lesions contained high concentrations of both TGF-ß isoforms. Smooth muscle cells (SMCs), macrophages, and foam cells of macrophage and SMC origin contributed to these high levels. These lesions also contained high, colocalized concentrations of ALK-5 and TßR-II. Despite fibrous plaques containing TGF-ß1, its receptors were at detection limits. We found no evidence for truncated TßR-II expression in either normal intima or the various atherosclerotic lesions.
Conclusions—TGF-ß appears to be most active in lipid-rich aortic intimal lesions. The findings support the hypothesis that TGF-ß contributes primarily to the pathogenesis of lipid-rich atherosclerotic lesions by stimulating the production of lipoprotein-trapping proteoglycans, inhibiting smooth muscle proliferation, and activating proteolytic mechanisms in macrophages.
Key Words: atherosclerosis • lesion • immunohistochemistry • cells • receptors
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