title: Class I HDACs regulate angiotensin II-dependent cardiac fibrosis via fibroblasts and circulating fibrocytes.
abstract: Fibrosis, which is defined as excessive accumulation of fibrous connective tissue, contributes to the pathogenesis of numerous diseases involving diverse organ systems. Cardiac fibrosis predisposes individuals to myocardial ischemia, arrhythmias and sudden death, and is commonly associated with diastolic dysfunction. Histone deacetylase (HDAC) inhibitors block cardiac fibrosis in pre-clinical models of heart failure. However, which HDAC isoforms govern cardiac fibrosis, and the mechanisms by which they do so, remains unclear. Here, we show that selective inhibition of class I HDACs potently suppresses angiotensin II (Ang II)-mediated cardiac fibrosis by targeting two key effector cell populations, cardiac fibroblasts and bone marrow-derived fibrocytes. Class I HDAC inhibition blocks cardiac fibroblast cell cycle progression through derepression of the genes encoding the cyclin-dependent kinase (CDK) inhibitors, p15 and p57. In contrast, class I HDAC inhibitors block agonist-dependent differentiation of fibrocytes through a mechanism involving repression of ERK1/2 signaling. These findings define novel roles for class I HDACs in the control of pathological cardiac fibrosis. Furthermore, since fibrocytes have been implicated in the pathogenesis of a variety of human diseases, including heart, lung and kidney failure, our results suggest broad utility for isoform-selective HDAC inhibitors as anti-fibrotic agents that function, in part, by targeting these circulating mesenchymal cells.
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Williams
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Golden-Mason
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Ferguson
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Schuetze
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Cavasin
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Demos-Davies
authors.affiliation: Department of Pediatrics, Division of Pulmonary and Critical Care Medicine, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Yeager
authors.affiliation: Department of Pediatrics, Division of Pulmonary and Critical Care Medicine, University of Colorado Denver, Aurora, CO, USA.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
authors.affiliation: Department of Medicine, Division of Cardiology, University of Colorado Denver, Aurora, CO, USA. Electronic address: timothy.mckinsey@ucdenver.edu.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy / Q000503:physiopathology*; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000494:pharmacology
chemical_list: D056572:Histone Deacetylase Inhibitors; D020033:Protein Isoforms; D000804:Angiotensin II
keywords: Fibroblast; Fibrocyte; Fibrosis; Histone deacetylase