HDAC6 contributes to pathological responses of heart and skeletal muscle to chronic angiotensin-II signaling.

Abstract

Little is known about the function of the cytoplasmic histone deacetylase HDAC6 in striated muscle. Here, we addressed the role of HDAC6 in cardiac and skeletal muscle remodeling induced by the peptide hormone angiotensin II (ANG II), which plays a central role in blood pressure control, heart failure, and associated skeletal muscle wasting. Comparable with wild-type (WT) mice, HDAC6 null mice developed cardiac hypertrophy and fibrosis in response to ANG II. However, whereas WT mice developed systolic dysfunction upon treatment with ANG II, cardiac function was maintained in HDAC6 null mice treated with ANG II for up to 8 wk. The cardioprotective effect of HDAC6 deletion was mimicked in WT mice treated with the small molecule HDAC6 inhibitor tubastatin A. HDAC6 null mice also exhibited improved left ventricular function in the setting of pressure overload mediated by transverse aortic constriction. HDAC6 inhibition appeared to preserve systolic function, in part, by enhancing cooperativity of myofibrillar force generation. Finally, we show that HDAC6 null mice are resistant to skeletal muscle wasting mediated by chronic ANG-II signaling. These findings define novel roles for HDAC6 in striated muscle and suggest potential for HDAC6-selective inhibitors for the treatment of cardiac dysfunction and muscle wasting in patients with heart failure.

• Authors: Kimberly M Demos-Davies, Bradley S Ferguson, Maria A Cavasin, Jennifer H Mahaffey, Sarah M Williams, Jessica I Spiltoir, Katherine B Schuetze, Todd R Horn, Bo Chen, Claudia Ferrara, Beatrice Scellini, Nicoletta Piroddi, Chiara Tesi, Corrado Poggesi, Mark Y Jeong, Timothy A McKinsey
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 307 Issue 2 Pg. H252-8 (Jul 15 2014) ISSN: 1522-1539 [Electronic] United States
• PMID: 24858848 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 the American Physiological Society.

Chemical References

• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Indoles
• Angiotensin II
• tubastatin A
• Hdac6 protein, mouse
• Histone Deacetylase 6
• Histone Deacetylases

Topics

• Angiotensin II
• Animals
• Cardiomegaly (chemically induced, enzymology, pathology, physiopathology, prevention & control)
• Disease Models, Animal
• Fibrosis
• Heart Failure (chemically induced, enzymology, pathology, physiopathology, prevention & control)
• Histone Deacetylase 6
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (deficiency, genetics, metabolism)
• Hydroxamic Acids (pharmacology)
• Indoles (pharmacology)
• Male
• Mice
• Mice, Knockout
• Muscle, Skeletal (drug effects, enzymology, pathology)
• Muscular Atrophy (chemically induced, enzymology, pathology, prevention & control)
• Myocardium (enzymology, pathology)
• Signal Transduction
• Stroke Volume
• Systole
• Time Factors
• Ventricular Function, Left
• Ventricular Remodeling