Cardiac histone acetylation--therapeutic opportunities abound.
Diverse etiologic factors trigger a cardiac remodeling process in which the heart becomes abnormally enlarged with a consequent decline in cardiac function and eventual heart failure. Heart failure is traditionally treated with drugs that antagonize early signaling events at or near the cell membrane. Although such approaches have short-term efficacy, the five-year mortality rate for patients with late-stage heart failure continues to exceed 50%. Because of the redundant nature of the signaling networks that drive cardiac pathogenesis, targeting the common downstream elements of the cascades would be a more effective therapeutic strategy. Recent studies point to the importance of enzymes that control histone acetylation as stress-responsive regulators of gene expression in the heart. Given their role as nuclear integrators that couple divergent upstream signals to the gene program for cardiac remodeling, we propose that these chromatin-modifying factors represent auspicious targets for the pharmacological manipulation of cardiac disease.
McKinsey
Timothy A
TA
Myogen, 7575 West 103rd Ave, Westminster, CO 80021, USA. timothy.mckinsey@myogen.com
Olson
Eric N
EN
D000107:Acetylation; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000628:therapy; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006984:Hypertrophy; D064326:MEF2 Transcription Factors; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008957:Models, Genetic; D009206:Myocardium / Q000166:cytology*; D018006:Myogenic Regulatory Factors; D009369:Neoplasms / Q000378:metabolism; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D002843:Chromatin; D004268:DNA-Binding Proteins; D006657:Histones; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D020033:Protein Isoforms; D014157:Transcription Factors; D006655:Histone Deacetylases