Toward transcriptional therapies for the failing heart: chemical screens to modulate genes.
In response to acute and chronic stresses, the heart frequently undergoes a remodeling process that is accompanied by myocyte hypertrophy, impaired contractility, and pump failure, often culminating in sudden death. The existence of redundant signaling pathways that trigger heart failure poses challenges for therapeutic intervention. Cardiac remodeling is associated with the activation of a pathological gene program that weakens cardiac performance. Thus, targeting the disease process at the level of gene expression represents a potentially powerful therapeutic approach. In this review, we describe strategies for normalizing gene expression in the failing heart with small molecules that control signal transduction pathways directed at transcription factors and associated chromatin-modifying enzymes.
McKinsey
Timothy A
TA
Myogen Inc., Westminster, Colorado 80021, USA. timothy.mckinsey@myogen.com
Olson
Eric N
EN
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002303:Cardiac Output, Low / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D064326:MEF2 Transcription Factors; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; C089212:protein kinase D; D011493:Protein Kinase C; D019703:Calcineurin; D006655:Histone Deacetylases