Skip to main content

Essential role for Smad3 in regulating MCP-1 expression and vascular inflammation.

Publication ,  Journal Article
Feinberg, MW; Shimizu, K; Lebedeva, M; Haspel, R; Takayama, K; Chen, Z; Frederick, JP; Wang, X-F; Simon, DI; Libby, P; Mitchell, RN; Jain, MK
Published in: Circ Res
March 19, 2004

Transforming growth factor (TGF)-beta(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-beta(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-beta(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-beta(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-beta(1) to repress stimuli from a major inflammatory signaling pathway.

Duke Scholars

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

March 19, 2004

Volume

94

Issue

5

Start / End Page

601 / 608

Location

United States

Related Subject Headings

  • Vasculitis
  • Tunica Intima
  • Transplantation, Homologous
  • Transforming Growth Factor beta1
  • Transforming Growth Factor beta
  • Transfection
  • Transcription, Genetic
  • Transcription Factor AP-1
  • Trans-Activators
  • Smad3 Protein
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Feinberg, M. W., Shimizu, K., Lebedeva, M., Haspel, R., Takayama, K., Chen, Z., … Jain, M. K. (2004). Essential role for Smad3 in regulating MCP-1 expression and vascular inflammation. Circ Res, 94(5), 601–608. https://doi.org/10.1161/01.RES.0000119170.70818.4F
Feinberg, Mark W., Koichi Shimizu, Maria Lebedeva, Richard Haspel, Kiyoshi Takayama, Zhiping Chen, Joshua P. Frederick, et al. “Essential role for Smad3 in regulating MCP-1 expression and vascular inflammation.Circ Res 94, no. 5 (March 19, 2004): 601–8. https://doi.org/10.1161/01.RES.0000119170.70818.4F.
Feinberg MW, Shimizu K, Lebedeva M, Haspel R, Takayama K, Chen Z, et al. Essential role for Smad3 in regulating MCP-1 expression and vascular inflammation. Circ Res. 2004 Mar 19;94(5):601–8.
Feinberg, Mark W., et al. “Essential role for Smad3 in regulating MCP-1 expression and vascular inflammation.Circ Res, vol. 94, no. 5, Mar. 2004, pp. 601–08. Pubmed, doi:10.1161/01.RES.0000119170.70818.4F.
Feinberg MW, Shimizu K, Lebedeva M, Haspel R, Takayama K, Chen Z, Frederick JP, Wang X-F, Simon DI, Libby P, Mitchell RN, Jain MK. Essential role for Smad3 in regulating MCP-1 expression and vascular inflammation. Circ Res. 2004 Mar 19;94(5):601–608.

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

March 19, 2004

Volume

94

Issue

5

Start / End Page

601 / 608

Location

United States

Related Subject Headings

  • Vasculitis
  • Tunica Intima
  • Transplantation, Homologous
  • Transforming Growth Factor beta1
  • Transforming Growth Factor beta
  • Transfection
  • Transcription, Genetic
  • Transcription Factor AP-1
  • Trans-Activators
  • Smad3 Protein