Faculty Collaboration Database

Transforming growth factor-beta1 inhibition of vascular smooth muscle cell activation is mediated via Smad3. J Biol Chem 2004 Apr 16;279(16):16388-93

Date

02/03/2004

Pubmed ID

14754879

DOI

10.1074/jbc.M309664200

Scopus ID

2-s2.0-11144355119 (requires institutional sign-in at Scopus site)   66 Citations

Abstract

Activation of vascular smooth muscle cells (VSMCs) by proinflammatory cytokines is a key feature of atherosclerotic lesion formation. Transforming growth factor (TGF)-beta1 is a pleiotropic growth factor that can modulate the inflammatory response in diverse cell types including VSMCs. However, the mechanisms by which TGF-beta1 is able to mediate these effects remains incompletely understood. We demonstrate here that the ability of TGF-beta1 to inhibit markers of VSMC activation, inducible nitric-oxide synthase (iNOS) and interleukin (IL)-6, is mediated through its downstream effector Smad3. In reporter gene transfection studies, we found that among a panel of Smads, Smad3 could inhibit iNOS induction in an analogous manner as exogenous TGF-beta1. Adenoviral overexpression of Smad3 potently repressed inducible expression of endogenous iNOS and IL-6. Conversely, TGF-beta1 inhibition of cytokine-mediated induction of iNOS and IL-6 expression was completely blocked in Smad3-deficient VSMCs. Previous studies demonstrate that CCAAT/enhancer-binding protein (C/EBP) and NF-kappaB sites are critical for cytokine induction of both the iNOS and IL-6 promoters. We demonstrate that the inhibitory effect of Smad3 occurs via a novel antagonistic effect of Smad3 on C/EBP DNA-protein binding and activity. Smad3 mediates this effect in part by inhibiting C/EBP-beta and C/EBP-delta through distinct mechanisms. Furthermore, we find that Smad3 prevents the cooperative induction of the iNOS promoter by C/EBP and NF-kappaB. These data demonstrate that Smad3 plays an essential role in mediating TGF-beta1 anti-inflammatory response in VSMCs.

Author List

Feinberg MW, Watanabe M, Lebedeva MA, Depina AS, Hanai J, Mammoto T, Frederick JP, Wang XF, Sukhatme VP, Jain MK

Author

Tadanori Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Arteriosclerosis
CCAAT-Enhancer-Binding Protein-delta
CCAAT-Enhancer-Binding Proteins
DNA-Binding Proteins
Inflammation
Muscle, Smooth, Vascular
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Rats
Signal Transduction
Smad3 Protein
Trans-Activators
Transcription Factors
Transforming Growth Factor beta
Transforming Growth Factor beta1