ArticleAmerican journal of physiology. Lung cellular and molecular physiology2012
Molecular mechanisms of MMP9 overexpression and its role in emphysema pathogenesis of Smad3-deficient mice.
Article in American journal of physiology. Lung cellular and molecular physiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
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- Proteomic insights into COPD pathogenesis and therapeutic targets: a causal analysis of circulating proteins.Frontiers in medicine · 2025Article
- Molecular changes underlying pulmonary emphysema and chronic bronchitis in Chronic Obstructive Pulmonary Disease: An updated review.Histology and histopathology · 2024Review
- Deflamin Attenuated Lung Tissue Damage in an Ozone-Induced COPD Murine Model by Regulating MMP-9 Catalytic Activity.International journal of molecular sciences · 2024Article
- Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies.Aging and disease · 2024Review
- Association of theArchives of medical science : AMS · 2024Review
- Recombinant Human HAPLN1 Mitigates Pulmonary Emphysema by Increasing TGF-β Receptor I and Sirtuins Levels in Human Alveolar Epithelial Cells.Molecules and cells · 2023Article
- Genetic Deletion ofInternational journal of molecular sciences · 2022Article
- Myofibroblast contraction is essential for generating and regenerating the gas-exchange surface.The Journal of clinical investigation · 2020Article
- Integrating multiomics longitudinal data to reconstruct networks underlying lung development.American journal of physiology. Lung cellular and molecular physiology · 2019Article
- Ursolic Acid Protected Lung of Rats From Damage Induced by Cigarette Smoke Extract.Frontiers in pharmacology · 2019Article
- Genetic polymorphism in matrix metalloproteinase-9 and transforming growth factor-β1 and susceptibility to combined pulmonary fibrosis and emphysema in a Chinese population.The Kaohsiung journal of medical sciences · 2017Article
- Reducing Smad3/ATF4 was essential for Sirt1 inhibiting ER stress-induced apoptosis in mice brown adipose tissue.Oncotarget · 2017Article
- Epigenetics in radiation-induced fibrosis.Oncogene · 2015Review
- Macrophage-specific NOX2 contributes to the development of lung emphysema through modulation of SIRT1/MMP-9 pathways.The Journal of pathology · 2015Article
- Sirt1, a negative regulator of matrix metalloproteinase-9 in diabetic retinopathy.Investigative ophthalmology & visual science · 2014Article
- Defining COPD-Related Comorbidities, 2004-2014.Chronic obstructive pulmonary diseases (Miami, Fla.) · 2014Review
- Glucocorticoids recruit Tgfbr3 and Smad1 to shift transforming growth factor-β signaling from the Tgfbr1/Smad2/3 axis to the Acvrl1/Smad1 axis in lung fibroblasts.The Journal of biological chemistry · 2014Article
- Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis.PloS one · 2014Article
- The Roles of SIRT1 in Cancer.Genes & cancer · 2013Article
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
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.
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