title: 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.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado;
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Demos-Davies
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado;
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Ferguson
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado;
authors.forename: Maria A
authors.initials: MA
authors.lastname: Cavasin
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado;
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Mahaffey
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado;
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Williams
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado;
authors.forename: Jessica I
authors.initials: JI
authors.lastname: Spiltoir
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado;
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Schuetze
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado;
authors.forename: Todd R
authors.initials: TR
authors.lastname: Horn
authors.affiliation: Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut; and.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Firenze, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Ferrara
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Firenze, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Scellini
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Firenze, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Piroddi
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Firenze, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Tesi
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Firenze, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Poggesi
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado;
authors.forename: Mark Y
authors.initials: MY
authors.lastname: Jeong
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, Colorado; timothy.mckinsey@ucdenver.edu.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
mesh_terms: D000804:Angiotensin II; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D005355:Fibrosis; D006333:Heart Failure / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009133:Muscular Atrophy / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction; D013318:Stroke Volume; D013599:Systole; D013997:Time Factors; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000804:Angiotensin II; C553587:tubastatin A; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: cardiac dysfunction; deacetylase; muscle atrophy