title: Inhibition of E2F abrogates the development of cardiac myocyte hypertrophy.
abstract: Growth of the post-natal mammalian heart occurs primarily by cardiac myocyte hypertrophy. Previously, we and others have shown that a partial re-activation of the cell cycle machinery occurs in myocytes undergoing hypertrophy such that cells progress through the G1/S transition. In this study, we have examined the regulation of the E2F family of transcription factors that are crucial for the G1/S phase transition during normal cardiac development and the development of myocyte hypertrophy in the rat. Thus, mRNA and protein levels of E2F-1, 3, and 4 and DP-1 and DP-2 were down-regulated during development to undetectable levels in adult myocytes. Interestingly, E2F-5 protein levels were substantially up-regulated during development. In contrast, an induction of E2F-1, 3, and 4 and the DP-1 protein was observed during the development of myocyte hypertrophy in neonatal myocytes treated with serum or phenylephrine, whereas the protein levels of E2F-5 were decreased with serum stimulation. E2F activity, as measured by a cyclin E promoter luciferase assay and E2F-DNA binding activity, increased significantly during the development of hypertrophy with serum and phenylephrine compared with non-stimulated cells. Inhibiting E2F activity with a specific peptide that blocks E2F-DP heterodimerization prevented the induction of hypertrophic markers (atrial natriuretic factor and brain natriuretic peptide) in response to serum and phenylephrine, reduced the increase in myocyte size, and inhibited protein synthesis in stimulated cells. Thus, we have shown that the inhibition of E2F function prevents the development of hypertrophy. Targeting E2F function might be a useful approach for treating diseases that cause pathophysiological hypertrophic growth.
authors.affiliation: Cardiovascular Research Group, School of Animal and Microbial Sciences, The University of Reading, Whiteknights, Reading, Berkshire RG6 6AJ, United Kingdom.
authors.forename: Dharmesh
authors.initials: D
authors.lastname: Vara
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Bicknell
authors.forename: Carmen H
authors.initials: CH
authors.lastname: Coxon
authors.forename: Gavin
authors.initials: G
authors.lastname: Brooks
mesh_terms: D016475:3T3 Cells; D000818:Animals; D018797:Cell Cycle Proteins; D019927:Cyclin E / Q000235:genetics; D004268:DNA-Binding Proteins; D019281:Dimerization; D015536:Down-Regulation; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050700:E2F5 Transcription Factor; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase; D006984:Hypertrophy; D017379:Hypertrophy, Left Ventricular; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000166:cytology* / Q000473:pathology*; D010455:Peptides / Q000737:chemistry; D010656:Phenylephrine / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012313:RNA / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050700:E2F5 Transcription Factor; C493754:E2f1 protein, mouse; C493755:E2f1 protein, rat; D010455:Peptides; D014157:Transcription Factors; D010656:Phenylephrine; D012313:RNA; D008156:Luciferases