NF-κB inhibition rescues cardiac function by remodeling calcium genes in a Duchenne muscular dystrophy model
| Autor: | Huating Wang, Jin Mo Gu, Jennifer M. Peterson, Sandya Liyanarachchi, Christopher E. Gaw, Vikram Shettigar, Mark T. Ziolo, Benjamin D. Canan, Jennifer M. Petrosino, Steve R. Roof, Sudarshana M. Sharma, Denis C. Guttridge, Nadine Bakkar, David J. Wang, Leina Lu, Paul M.L. Janssen, Jonathan P. Davis, Sean C. Little, Priya Londhe, Jonathan Shintaku, Nivedita M. Ratnam |
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| Rok vydání: | 2018 |
| Předmět: |
Male
musculoskeletal diseases 0301 basic medicine CCCTC-Binding Factor Science Duchenne muscular dystrophy Cardiomyopathy General Physics and Astronomy Histone Deacetylase 1 Article Sodium-Calcium Exchanger General Biochemistry Genetics and Molecular Biology Muscle hypertrophy Mice 03 medical and health sciences 0302 clinical medicine Animals Medicine Myocyte Myocytes Cardiac Muscular dystrophy lcsh:Science Cells Cultured Multidisciplinary business.industry NF-kappa B Skeletal muscle General Chemistry Chromatin Assembly and Disassembly medicine.disease HDAC1 Cell biology Chromatin Muscular Dystrophy Duchenne Repressor Proteins Sin3 Histone Deacetylase and Corepressor Complex 030104 developmental biology medicine.anatomical_structure Mice Inbred mdx Calcium lcsh:Q business 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-14 (2018) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Duchenne muscular dystrophy (DMD) is a neuromuscular disorder causing progressive muscle degeneration. Although cardiomyopathy is a leading mortality cause in DMD patients, the mechanisms underlying heart failure are not well understood. Previously, we showed that NF-κB exacerbates DMD skeletal muscle pathology by promoting inflammation and impairing new muscle growth. Here, we show that NF-κB is activated in murine dystrophic (mdx) hearts, and that cardiomyocyte ablation of NF-κB rescues cardiac function. This physiological improvement is associated with a signature of upregulated calcium genes, coinciding with global enrichment of permissive H3K27 acetylation chromatin marks and depletion of the transcriptional repressors CCCTC-binding factor, SIN3 transcription regulator family member A, and histone deacetylase 1. In this respect, in DMD hearts, NF-κB acts differently from its established role as a transcriptional activator, instead promoting global changes in the chromatin landscape to regulate calcium genes and cardiac function. The molecular mechanisms leading to heart failure in patients with Duchenne muscular dystrophy are unclear. Here the authors show that NF-κB is activated in the heart of dystrophin-deficient mice and that its ablation rescues cardiac function through chromatin remodeling and activation of gene expression. |
| Databáze: | OpenAIRE |
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