| First Author | Xu B | Year | 2012 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 303 |
| Issue | 2 | Pages | L89-96 |
| PubMed ID | 22610349 | Mgi Jnum | J:191358 |
| Mgi Id | MGI:5461595 | Doi | 10.1152/ajplung.00060.2012 |
| Citation | Xu B, et al. (2012) Molecular mechanisms of MMP9 overexpression and its role in emphysema pathogenesis of Smad3-deficient mice. Am J Physiol Lung Cell Mol Physiol 303(2):L89-96 |
| abstractText | 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-kappaB, and Pea3 binding sites of MMP9 promoter and increased acetylation of NF-kappaB. In addition, increased Pea3 expression and nuclear accumulation was also detected in Smad3-null lungs at P28. Consistently, bindings of acetylated NF-kappaB 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-kappaB. Subsequently, increased bindings of transcription factors including NF-kappaB and Pea3 to MMP9 promoter significantly upregulate MMP9 transcription, contributing to emphysema pathogenesis. |
