Molecular mechanisms of MMP9 overexpression and its role in emphysema pathogenesis of Smad3-deficient mice

Bing Xu, Hui Chen, Wei Xu, Wenming Zhang, Sue Buckley, Song Guo Zheng, David Warburton, Martin Kolb, Jack Gauldie, Wei Shi

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Previous studies have found that inappropriate elevation of matrix metalloproteinase-9 (MMP9) ex-pression and activity is coincident with early onset of emphysema in Smad3-null mice. Herein, we further investigated the role of increased MMP9 in emphysema pathogenesis and the related molecular regu-latory mechanisms of elevated MMP9 in Smad3-null lung. Genetic blockade of MMP9 in Smad3-null mice significantly attenuated em-physema pathology but not hypoalveolarization during early postnatal lung development. Furthermore, Smad3 was found to be a transcrip-tion factor to positively regulate a protein deacetylase sirtuin 1 (SIRT1) by binding to an AP-1 site of SIRT1 promoter. A synergistic regulatory effect on SIRT1 expression was also detected between Smad3 and c-Jun. Consistently, Smad3 knockout lung at P28 had reduced SIRT1 expression, which in turn resulted in increased acetylation of histone H3 at the transcription factor activator protein 1 (AP-1), NF-κB, and Pea3 binding sites of MMP9 pro-moter and increased acetylation of NF-κB. In addition, increased Pea3 expression and nuclear accumulation was also detected in Smad3-null lungs at P28. Consistently, bindings of acetylated NF-κB and Pea3 to the MMP9 promoter were elevated in Smad3-null lung. We thus propose that deficiency of Smad3 causes downregulation of SIRT1 and increased Pea3 expression/nuclear accumulation, respectively. Decreased SIRT1 activity resulted in increased acetylation of histone H3 and NF-κB. Subsequently, increased bindings of transcription factors including NF-κB and Pea3 to MMP9 promoter significantly upregulate MMP9 transcrip-tion, contributing to emphysema pathogenesis.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume303
Issue number2
DOIs
StatePublished - Jul 15 2012

Fingerprint

Sirtuin 1
Matrix Metalloproteinase 9
Emphysema
Acetylation
Lung
Transcription Factor AP-1
Histones
Transcription Factors
Up-Regulation
Down-Regulation
Binding Sites
Pathology

Keywords

  • Matrix metalloproteinase-9
  • NF-κB
  • Pea3
  • Sirtuin 1

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Molecular mechanisms of MMP9 overexpression and its role in emphysema pathogenesis of Smad3-deficient mice. / Xu, Bing; Chen, Hui; Xu, Wei; Zhang, Wenming; Buckley, Sue; Zheng, Song Guo; Warburton, David; Kolb, Martin; Gauldie, Jack; Shi, Wei.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 303, No. 2, 15.07.2012.

Research output: Contribution to journalArticle

Xu, Bing ; Chen, Hui ; Xu, Wei ; Zhang, Wenming ; Buckley, Sue ; Zheng, Song Guo ; Warburton, David ; Kolb, Martin ; Gauldie, Jack ; Shi, Wei. / Molecular mechanisms of MMP9 overexpression and its role in emphysema pathogenesis of Smad3-deficient mice. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2012 ; Vol. 303, No. 2.
@article{8e6e2c16b6fa4ca3b49c9c3ae7eb7d0c,
title = "Molecular mechanisms of MMP9 overexpression and its role in emphysema pathogenesis of Smad3-deficient mice",
abstract = "Previous studies have found that inappropriate elevation of matrix metalloproteinase-9 (MMP9) ex-pression and activity is coincident with early onset of emphysema in Smad3-null mice. Herein, we further investigated the role of increased MMP9 in emphysema pathogenesis and the related molecular regu-latory mechanisms of elevated MMP9 in Smad3-null lung. Genetic blockade of MMP9 in Smad3-null mice significantly attenuated em-physema pathology but not hypoalveolarization during early postnatal lung development. Furthermore, Smad3 was found to be a transcrip-tion factor to positively regulate a protein deacetylase sirtuin 1 (SIRT1) by binding to an AP-1 site of SIRT1 promoter. A synergistic regulatory effect on SIRT1 expression was also detected between Smad3 and c-Jun. Consistently, Smad3 knockout lung at P28 had reduced SIRT1 expression, which in turn resulted in increased acetylation of histone H3 at the transcription factor activator protein 1 (AP-1), NF-κB, and Pea3 binding sites of MMP9 pro-moter and increased acetylation of NF-κB. In addition, increased Pea3 expression and nuclear accumulation was also detected in Smad3-null lungs at P28. Consistently, bindings of acetylated NF-κB and Pea3 to the MMP9 promoter were elevated in Smad3-null lung. We thus propose that deficiency of Smad3 causes downregulation of SIRT1 and increased Pea3 expression/nuclear accumulation, respectively. Decreased SIRT1 activity resulted in increased acetylation of histone H3 and NF-κB. Subsequently, increased bindings of transcription factors including NF-κB and Pea3 to MMP9 promoter significantly upregulate MMP9 transcrip-tion, contributing to emphysema pathogenesis.",
keywords = "Matrix metalloproteinase-9, NF-κB, Pea3, Sirtuin 1",
author = "Bing Xu and Hui Chen and Wei Xu and Wenming Zhang and Sue Buckley and Zheng, {Song Guo} and David Warburton and Martin Kolb and Jack Gauldie and Wei Shi",
year = "2012",
month = "7",
day = "15",
doi = "10.1152/ajplung.00060.2012",
language = "English (US)",
volume = "303",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "2",

}

TY - JOUR

T1 - Molecular mechanisms of MMP9 overexpression and its role in emphysema pathogenesis of Smad3-deficient mice

AU - Xu, Bing

AU - Chen, Hui

AU - Xu, Wei

AU - Zhang, Wenming

AU - Buckley, Sue

AU - Zheng, Song Guo

AU - Warburton, David

AU - Kolb, Martin

AU - Gauldie, Jack

AU - Shi, Wei

PY - 2012/7/15

Y1 - 2012/7/15

N2 - Previous studies have found that inappropriate elevation of matrix metalloproteinase-9 (MMP9) ex-pression and activity is coincident with early onset of emphysema in Smad3-null mice. Herein, we further investigated the role of increased MMP9 in emphysema pathogenesis and the related molecular regu-latory mechanisms of elevated MMP9 in Smad3-null lung. Genetic blockade of MMP9 in Smad3-null mice significantly attenuated em-physema pathology but not hypoalveolarization during early postnatal lung development. Furthermore, Smad3 was found to be a transcrip-tion factor to positively regulate a protein deacetylase sirtuin 1 (SIRT1) by binding to an AP-1 site of SIRT1 promoter. A synergistic regulatory effect on SIRT1 expression was also detected between Smad3 and c-Jun. Consistently, Smad3 knockout lung at P28 had reduced SIRT1 expression, which in turn resulted in increased acetylation of histone H3 at the transcription factor activator protein 1 (AP-1), NF-κB, and Pea3 binding sites of MMP9 pro-moter and increased acetylation of NF-κB. In addition, increased Pea3 expression and nuclear accumulation was also detected in Smad3-null lungs at P28. Consistently, bindings of acetylated NF-κB and Pea3 to the MMP9 promoter were elevated in Smad3-null lung. We thus propose that deficiency of Smad3 causes downregulation of SIRT1 and increased Pea3 expression/nuclear accumulation, respectively. Decreased SIRT1 activity resulted in increased acetylation of histone H3 and NF-κB. Subsequently, increased bindings of transcription factors including NF-κB and Pea3 to MMP9 promoter significantly upregulate MMP9 transcrip-tion, contributing to emphysema pathogenesis.

AB - Previous studies have found that inappropriate elevation of matrix metalloproteinase-9 (MMP9) ex-pression and activity is coincident with early onset of emphysema in Smad3-null mice. Herein, we further investigated the role of increased MMP9 in emphysema pathogenesis and the related molecular regu-latory mechanisms of elevated MMP9 in Smad3-null lung. Genetic blockade of MMP9 in Smad3-null mice significantly attenuated em-physema pathology but not hypoalveolarization during early postnatal lung development. Furthermore, Smad3 was found to be a transcrip-tion factor to positively regulate a protein deacetylase sirtuin 1 (SIRT1) by binding to an AP-1 site of SIRT1 promoter. A synergistic regulatory effect on SIRT1 expression was also detected between Smad3 and c-Jun. Consistently, Smad3 knockout lung at P28 had reduced SIRT1 expression, which in turn resulted in increased acetylation of histone H3 at the transcription factor activator protein 1 (AP-1), NF-κB, and Pea3 binding sites of MMP9 pro-moter and increased acetylation of NF-κB. In addition, increased Pea3 expression and nuclear accumulation was also detected in Smad3-null lungs at P28. Consistently, bindings of acetylated NF-κB and Pea3 to the MMP9 promoter were elevated in Smad3-null lung. We thus propose that deficiency of Smad3 causes downregulation of SIRT1 and increased Pea3 expression/nuclear accumulation, respectively. Decreased SIRT1 activity resulted in increased acetylation of histone H3 and NF-κB. Subsequently, increased bindings of transcription factors including NF-κB and Pea3 to MMP9 promoter significantly upregulate MMP9 transcrip-tion, contributing to emphysema pathogenesis.

KW - Matrix metalloproteinase-9

KW - NF-κB

KW - Pea3

KW - Sirtuin 1

UR - http://www.scopus.com/inward/record.url?scp=84863898701&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863898701&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00060.2012

DO - 10.1152/ajplung.00060.2012

M3 - Article

VL - 303

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 2

ER -