Dose-dependent blockade to cardiomyocyte hypertrophy by histone deacetylase inhibitors.
Postnatal cardiac myocytes respond to stress signals by hypertrophic growth and activation of a fetal gene program. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy, and mice lacking the class II HDAC, HDAC9, are sensitized to hypertrophic signals. To further define the roles of HDACs in cardiac hypertrophy, we analyzed the effects of HDAC inhibitors on the responsiveness of primary cardiomyocytes to hypertrophic agonists. Paradoxically, HDAC inhibitors imposed a dose-dependent blockade to hypertrophy and fetal gene activation. We conclude that distinct HDACs play positive or negative roles in the control of cardiomyocyte hypertrophy. HDAC inhibitors are currently being tested in clinical trials as anti-cancer agents. Our results suggest that these inhibitors may also hold promising clinical value as therapeutics for cardiac hypertrophy and heart failure.
Antos
Christopher L
CL
Department of Molecular Biology, The University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas 75390-9148, USA.
McKinsey
Timothy A
TA
Dreitz
Matthew
M
Hollingsworth
Lisa M
LM
Zhang
Chun-Li
CL
Schreiber
Kathy
K
Rindt
Hansjorg
H
Gorczynski
Richard J
RJ
Olson
Eric N
EN
D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000032:analysis / Q000235:genetics; D006332:Cardiomegaly / Q000517:prevention & control*; D002478:Cells, Cultured; D004247:DNA / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005333:Fetus; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D007930:Leucine / Q000378:metabolism; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium; D024723:Ventricular Myosins / Q000235:genetics
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D014316:Tritium; D009320:Atrial Natriuretic Factor; D004247:DNA; D000263:Adenylate Kinase; D006655:Histone Deacetylases; D024723:Ventricular Myosins; D007930:Leucine