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First published online 18 September 2007
doi: 10.1242/jcs.006916

Journal of Cell Science 120, 3509-3521 (2007)
Published by The Company of Biologists 2007
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Research Article

Cholesterol suppresses cellular TGF-beta responsiveness: implications in atherogenesis

Chun-Lin Chen1, I-Hua Liu2, Steven J. Fliesler3, Xianlin Han4, Shuan Shian Huang2 and Jung San Huang1,*

1 Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, 1402 S. Grand Blvd., St Louis, MO 63104, USA
2 Auxagen Inc., 7 Pricewoods, St Louis, MO 63132, USA
3 Departments of Ophthalmology and Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 S. Grand Blvd., St Louis, MO 63104, USA
4 Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA

* Author for correspondence (e-mail: huangjs{at}slu.edu)

Accepted 22 July 2007

Hypercholesterolemia is a major causative factor for atherosclerotic cardiovascular disease. The molecular mechanisms by which cholesterol initiates and facilitates the process of atherosclerosis are not well understood. Here, we demonstrate that cholesterol treatment suppresses or attenuates TGF-beta responsiveness in all cell types studied as determined by measuring TGF-beta-induced Smad2 phosphorylation and nuclear translocation, TGF-beta-induced PAI-1 expression, TGF-beta-induced luciferase reporter gene expression and TGF-beta-induced growth inhibition. Cholesterol, alone or complexed in lipoproteins (LDL, VLDL), suppresses TGF-beta responsiveness by increasing lipid raft and/or caveolae accumulation of TGF-beta receptors and facilitating rapid degradation of TGF-beta and thus suppressing TGF-beta-induced signaling. Conversely, cholesterol-lowering agents (fluvastatin and lovastatin) and cholesterol-depleting agents (beta-cyclodextrin and nystatin) enhance TGF-beta responsiveness by increasing non-lipid raft microdomain accumulation of TGF-beta receptors and facilitating TGF-beta-induced signaling. Furthermore, the effects of cholesterol on the cultured cells are also found in the aortic endothelium of ApoE-null mice fed a high-cholesterol diet. These results suggest that high cholesterol contributes to atherogenesis, at least in part, by suppressing TGF-beta responsiveness in vascular cells.

Key words: Cholesterol, TGF-beta, TGF-beta receptors


Related articles in JCS:

Atherogenesis: cholesterol quashes TGF-beta

JCS 2007 120: 2001. [Full Text]  





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