title: Signal-dependent repression of DUSP5 by class I HDACs controls nuclear ERK activity and cardiomyocyte hypertrophy.
abstract: Cardiac hypertrophy is a strong predictor of morbidity and mortality in patients with heart failure. Small molecule histone deacetylase (HDAC) inhibitors have been shown to suppress cardiac hypertrophy through mechanisms that remain poorly understood. We report that class I HDACs function as signal-dependent repressors of cardiac hypertrophy via inhibition of the gene encoding dual-specificity phosphatase 5 (DUSP5) DUSP5, a nuclear phosphatase that negatively regulates prohypertrophic signaling by ERK1/2. Inhibition of DUSP5 by class I HDACs requires activity of the ERK kinase, mitogen-activated protein kinase kinase (MEK), revealing a self-reinforcing mechanism for promotion of cardiac ERK signaling. In cardiac myocytes treated with highly selective class I HDAC inhibitors, nuclear ERK1/2 signaling is suppressed in a manner that is absolutely dependent on DUSP5. In contrast, cytosolic ERK1/2 activation is maintained under these same conditions. Ectopic expression of DUSP5 in cardiomyocytes results in potent inhibition of agonist-dependent hypertrophy through a mechanism involving suppression of the gene program for hypertrophic growth. These findings define unique roles for class I HDACs and DUSP5 as integral components of a regulatory signaling circuit that controls cardiac hypertrophy.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Ferguson
authors.forename: Brooke C
authors.initials: BC
authors.lastname: Harrison
authors.forename: Mark Y
authors.initials: MY
authors.lastname: Jeong
authors.forename: Brian G
authors.initials: BG
authors.lastname: Reid
authors.forename: Michael F
authors.initials: MF
authors.lastname: Wempe
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001549:Benzamides / Q000494:pharmacology; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology; D002478:Cells, Cultured; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D015151:Immunoblotting; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D011743:Pyrimidines; C523184:mocetinostat; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054637:Dual-Specificity Phosphatases; C514214:Dusp5 protein, rat; D006655:Histone Deacetylases
keywords: cardiac remodeling; gene transcription; lysine acetylation