Dual roles of histone deacetylases in the control of cardiac growth.
Diverse aetiological factors, including myocardial infarction, hypertension and contractile abnormalities, trigger a cardiac remodelling process in which the heart becomes abnormally enlarged with a consequent decline in cardiac function and eventual heart failure. Pathological cardiac hypertrophy is accompanied by the activation of a fetal cardiac gene programme, which contributes to maladaptive changes in contractility and calcium handling. Traditional treatment for heart failure involves administration of drugs that antagonize early signalling events at or near the cell membrane (e.g. cell surface receptor or ion channels). Given the complexity and redundant nature of the signalling networks that drive cardiac pathogenesis, a potentially more efficacious therapeutic strategy for disrupting the disease process would be to target common downstream elements in pathological signalling cascades. We have shown that class II histone deacetylases (HDACs) suppress cardiac hypertrophy, and mice lacking class II HDACs are sensitized to hypertrophic signals. Paradoxically, HDAC inhibitors also block cardiac hypertrophy and fetal gene activation. Based on these findings, we propose that distinct HDACs play positive or negative roles in the control of cardiac growth by regulating opposing sets of target genes via their interactions with different sets of transcription factors.
McKinsey
Timothy A
TA
Myogen, Inc., 7575 West 103rd Avenue, Westminster, CO 80021, USA.
Olson
Eric N
EN
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000254:growth & development*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D006657:Histones; D012097:Repressor Proteins; D019703:Calcineurin; C486545:Hdac9 protein, mouse; D006655:Histone Deacetylases