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

Previous studies have found that inappropriate elevation of matrix metalloproteinase-9 (MMP9) expression 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 regulatory mechanisms of elevated MMP9 in Smad3-null lung. Genetic blockade of MMP9 in Smad3-null mice significantly attenuated emphysema pathology but not hypoalveolarization during early postnatal lung development. Furthermore, Smad3 was found to be a transcription 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 promoter 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 transcription, contributing to emphysema pathogenesis.

Pubmed ID: 22610349

Authors

  • Xu B
  • Chen H
  • Xu W
  • Zhang W
  • Buckley S
  • Zheng SG
  • Warburton D
  • Kolb M
  • Gauldie J
  • Shi W

Journal

American journal of physiology. Lung cellular and molecular physiology

Publication Data

July 16, 2012

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL068597
  • Agency: NHLBI NIH HHS, Id: HL109932
  • Agency: NIGMS NIH HHS, Id: R01 GM096195

Mesh Terms

  • Acetylation
  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Line
  • Gene Expression
  • Gene Expression Regulation, Enzymologic
  • Histones
  • JNK Mitogen-Activated Protein Kinases
  • Lung
  • Matrix Metalloproteinase 9
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • NF-kappa B
  • Promoter Regions, Genetic
  • Protein Binding
  • Pulmonary Emphysema
  • Signal Transduction
  • Sirtuin 1
  • Smad3 Protein
  • Transcription Factor AP-1
  • Transcription Factors
  • Transcription, Genetic
  • Transforming Growth Factor beta1
  • Up-Regulation