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(Circulation Research. 2004;94:601.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Essential Role for Smad3 in Regulating MCP-1 Expression and Vascular Inflammation

Mark W. Feinberg, Koichi Shimizu, Maria Lebedeva, Richard Haspel, Kiyoshi Takayama, Zhiping Chen, Joshua P. Frederick, Xiao-Fan Wang, Daniel I. Simon, Peter Libby, Richard N. Mitchell, Mukesh K. Jain

From the Division of Cardiovascular Medicine (M.W.F., K.S., M.L., K.T., Z.C., D.I.S., P.L., M.K.J.) and Department of Pathology (R.H., R.N.M.), Brigham and Women’s Hospital, Boston, Mass; Duke University (J.P.F., X.-F.W.), Durham, NC.

Correspondence to Mark W. Feinberg and Mukesh K. Jain, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail mfeinberg{at}rics.bwh.harvard.edu and mjain@rics.bwh.harvard.edu

Transforming growth factor (TGF)-ß₁ is a pleiotropic growth factor with known inhibitory effects on immune cell activation. However, the specific mechanism(s) and in vivo significance of the effectors of TGF-ß₁ modulation in the context of vascular inflammation are not well characterized. The chemokine monocyte chemoattractant protein (MCP)-1 is critical for the recruitment of macrophages in inflammatory disease states. In this study, we provide definitive evidence that the ability of TGF-ß₁ to inhibit MCP-1 expression is mediated via its effector Smad3. Adenoviral overexpression of Smad3 potently repressed inducible expression of endogenous MCP-1. Conversely, TGF-ß₁ inhibition of cytokine-mediated induction of MCP-1 expression was completely blocked in Smad3-deficient macrophages. Consistent with this impaired response, cardiac allografts in Smad3-deficient mice developed accelerated intimal hyperplasia with increased infiltration of adventitial macrophages expressing MCP-1. Previous studies show that MCP-1 inducibility is regulated by an AP-1 complex composed of c-Jun/c-Fos heterodimers. We demonstrate that the inhibitory effect of Smad3 occurs via a novel antagonistic effect of Smad3 on AP-1 DNA-protein binding and activity. Thus, Smad3 plays an essential role in modulating vascular inflammation characteristic of transplant-associated arteriopathy, is important in regulating MCP-1 expression, and plays a critical role in the ability of TGF-ß₁ to repress stimuli from a major inflammatory signaling pathway.

Key Words: transforming growth factor-ß • Smads • vascular inflammation • AP-1 • atherosclerosis

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