title: The E2F6 repressor activates gene expression in myocardium resulting in dilated cardiomyopathy.
abstract: The E2F/Rb pathway regulates cardiac growth and development and holds great potential as a therapeutic target. The E2F6 repressor is a unique E2F member that acts independently of pocket proteins. Forced expression of E2F6 in mouse myocardium induced heart failure and mortality, with severity of symptoms correlating to E2F6 levels. Echocardiography demonstrated a 37% increase (P<0.05) in left ventricular end-diastolic diameter and reduced ejection fraction (<40%, P<0.05) in young transgenic (Tg) mice. Microarray and qPCR analysis revealed a paradoxical increase in E2F-responsive genes, which regulate the cell cycle, without changes in cardiomyocyte cell number or size in Tg mice. Young adult Tg mice displayed a 75% (P<0.01) decrease in gap junction protein connexin-43, resulting in abnormal electrocardiogram including a 24% (P<0.05) increase in PR interval. Further, mir-206, which targets connexin-43, was up-regulated 10-fold (P<0.05) in Tg myocardium. The mitogen-activated protein kinase pathway, which regulates the levels of miR-206 and connexin-43, was activated in Tg hearts. Thus, deregulated E2F6 levels evoked abnormal gene expression at transcriptional and post-transcriptional levels, leading to cardiac remodeling and dilated cardiomyopathy. The data highlight an unprecedented role for the strict regulation of the E2F pathway in normal postnatal cardiac function.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Rd., Ottawa, ON K1H 8M5, Canada.
authors.forename: Bart
authors.initials: B
authors.lastname: Westendorp
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Major
authors.forename: Moni
authors.initials: M
authors.lastname: Nader
authors.forename: Maysoon
authors.initials: M
authors.lastname: Salih
authors.forename: Frans H H
authors.initials: FH
authors.lastname: Leenen
authors.forename: Balwant S
authors.initials: BS
authors.lastname: Tuana
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000209:etiology*; D018031:Connexin 43 / Q000096:biosynthesis; D015536:Down-Regulation; D050701:E2F6 Transcription Factor / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism
chemical_list: D018031:Connexin 43; D050701:E2F6 Transcription Factor; C543076:GJA1 protein, mouse