| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Robbins, Jeffrey James, Jeanne Mckinsey, Timothy A. Ferguson, Bradley S. Bhuiyan, Md Shenuarin Mclendon, Patrick M. Osinska, Hanna |
| Description |
Author Affiliation: McLendon PM ( The Heart Institute, Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229); Ferguson BS ( Department of Medicine, Division of Cardiology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045.); Osinska H ( The Heart Institute, Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229); Bhuiyan MS ( The Heart Institute, Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229); James J ( The Heart Institute, Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229); McKinsey TA ( Department of Medicine, Division of Cardiology, Anschutz Medical Campus, University of Colorado Denver, Aurora, CO 80045.); Robbins J ( The Heart Institute, Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229); |
| Abstract |
Proteinopathy causes cardiac disease, remodeling, and heart failure but the pathological mechanisms remain obscure. Mutated B-crystallin (CryAB(R120G)), when expressed only in cardiomyocytes in transgenic (TG) mice, causes desmin-related cardiomyopathy, a protein conformational disorder. The disease is characterized by the accumulation of toxic misfolded protein species that present as perinuclear aggregates known as aggresomes. Previously, we have used the CryAB(R120G) model to determine the underlying processes that result in these pathologic accumulations and to explore potential therapeutic windows that might be used to decrease proteotoxicity. We noted that total ventricular protein is hypoacetylated while hyperacetylation of -tubulin, a substrate of histone deacetylase 6 (HDAC6) occurs. HDAC6 has critical roles in protein trafficking and autophagy, but its function in the heart is obscure. Here, we test the hypothesis that tubulin acetylation is an adaptive process in cardiomyocytes. By modulating HDAC6 levels and/or activity genetically and pharmacologically, we determined the effects of tubulin acetylation on aggregate formation in CryAB(R120G) cardiomyocytes. Increasing HDAC6 accelerated aggregate formation, whereas siRNA-mediated knockdown or pharmacological inhibition ameliorated the process. HDAC inhibition in vivo induced tubulin hyperacetylation in CryAB(R120G) TG hearts, which prevented aggregate formation and significantly improved cardiac function. HDAC6 inhibition also increased autophagic flux in cardiomyocytes, and increased autophagy in the diseased heart correlated with increased tubulin acetylation, suggesting that autophagy induction might underlie the observed cardioprotection. Taken together, our data suggest a mechanistic link between tubulin hyperacetylation and autophagy induction and points to HDAC6 as a viable therapeutic target in cardiovascular disease. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
48 |
| Volume Number |
111 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2014-12-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Adaptation, Physiological Autophagy Myocardium Metabolism Tubulin Acetylation Drug Effects Animals Animals, Newborn Cells, Cultured Heart Physiology Histone Deacetylase Inhibitors Pharmacology Histone Deacetylases Hydroxamic Acids Immunoblotting Immunohistochemistry Mice, Transgenic Microscopy, Electron Mutation Cytology Ultrastructure Myocytes, Cardiac Primary Cell Culture Rats, Sprague-Dawley Alpha-Crystallin B Chain Genetics Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
