Published online before print January 29, 2004, doi: 10.1161/01.RES.0000119170.70818.4F
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Submitted on July 8, 2003
Revised on January 15, 2004
Accepted on January 16, 2004
Essential Role for Smad3 in Regulating MCP-1 Expression and Vascular Inflammation
Mark W. Feinberg *;
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.
* To whom correspondence should be addressed. E-mail: mfeinberg{at}rics.bwh.harvard.edu.
Transforming growth factor (TGF)-
1 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-1 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-1 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-1 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-1 to repress stimuli from a major inflammatory signaling pathway.
Key words: transforming growth factor-
•
Smads •
vascular inflammation •
AP-1 •
atherosclerosis
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