Cardiac HDAC6 catalytic activity is induced in response to chronic hypertension
| Autor: | Timothy A. McKinsey, Sylvia A. McCune, Leslie A. Leinwand, Maria A. Cavasin, David Irwin, Todd R. Horn, Mark Y. Jeong, Douglas D. Lemon, Carlin S. Long, Eunhee Chung, Kurt W. Haubold |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Gene isoform medicine.medical_specialty Heart Ventricles Biology Pharmacology Histone Deacetylase 6 Polymerase Chain Reaction Article Histone Deacetylases Adenoviridae Rats Sprague-Dawley Mice Internal medicine medicine Animals Protein Isoforms Myocyte Myocytes Cardiac RNA Small Interfering Ventricular remodeling Molecular Biology Cells Cultured Ventricular Remodeling Myocardium HDAC6 medicine.disease Hypertensive heart disease Rats Histone Deacetylase Inhibitors Endocrinology Cardiovascular Diseases Heart failure Hypertension RNA Interference Histone deacetylase Signal transduction Cardiology and Cardiovascular Medicine Signal Transduction |
| Zdroj: | Journal of Molecular and Cellular Cardiology. 51:41-50 |
| ISSN: | 0022-2828 |
| DOI: | 10.1016/j.yjmcc.2011.04.005 |
| Popis: | Small molecule histone deacetylase (HDAC) inhibitors block adverse cardiac remodeling in animal models of heart failure. The efficacious compounds target class I, class IIb and, to a lesser extent, class IIa HDACs. It is hypothesized that a selective inhibitor of a specific HDAC class (or an isoform within that class) will provide a favorable therapeutic window for the treatment of heart failure, although the optimal selectivity profile for such a compound remains unknown. Genetic studies have suggested that class I HDACs promote pathological cardiac remodeling, while class IIa HDACs are protective. In contrast, nothing is known about the function or regulation of class IIb HDACs in the heart. We developed assays to quantify catalytic activity of distinct HDAC classes in left and right ventricular cardiac tissue from animal models of hypertensive heart disease. Class I and IIa HDAC activity was elevated in some but not all diseased tissues. In contrast, catalytic activity of the class IIb HDAC, HDAC6, was consistently increased in stressed myocardium, but not in a model of physiologic hypertrophy. HDAC6 catalytic activity was also induced by diverse extracellular stimuli in cultured cardiac myocytes and fibroblasts. These findings suggest an unforeseen role for HDAC6 in the heart, and highlight the need for pre-clinical evaluation of HDAC6-selective inhibitors to determine whether this HDAC isoform is pathological or protective in the setting of cardiovascular disease. |
| Databáze: | OpenAIRE |
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