title: The role of E2F1 in the development of hypertrophic cardiomyopathy.
abstract: The overexpression of the transcription factor, E2F1, induces hypertrophy and apoptosis with cell cycle re-entry in cardiomyocytes in vitro and in vivo, suggesting that targeting E2F1 may have therapeutic potential. Accordingly, we tested the hypothesis that blocking the E2F1-mediated signal transduction pathway prevents cardiac hypertrophy by treating E2F1 knockout mice (E2F1-/-) with either isoproterenol (ISO) or Angiotensin II (ANG). Echocardi-ography was used to measure left ventricular mass index and myocardial performance index, a measure of combined systolic and diastolic left ventricular function. In control mice (E2F1+/+) both ISO and ANG treatments induced cardiac hypertrophy, and impaired ventricular function in ANG treated mice. In contrast to previously published work, E2F1-/- mice also demonstrated a similar pattern of cardiac hypertrophy and function after either treatment. Atrial natriuretic peptide, a molecular marker of hypertrophy and necropsy-determined body weight-normalized left ventricle mass were similarly increased in ISO and ANG treated E2F1+/+ and E2F-/- mice, supporting the echocardiographic data. These data indicate that E2F1 is not necessary for the development of cardiac hypertrophy although studies using an overexpression approach suggest a causal role of E2F1. The reason for this discrepancy is unclear, although it is possible that other E2F-family members (e.g., E2F2) may play a compensatory role. In conclusion, our data demonstrate that cardiac hypertrophy can be induced in an E2F1-independent fashion and suggest that in contrast to previous reports, targeting E2F1 may not be a good therapeutic approach.
authors: Departments of Pathology and 2Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Julie A
authors: JA
authors: Wolfram
authors: Anna
authors: A
authors: Liner
authors: Sandy L
authors: SL
authors: Richardson
authors: Xiongwei
authors: X
authors: Zhu
authors: Mark A
authors: MA
authors: Smith
authors: Brian D
authors: BD
authors: Hoit
authors: Hyoung-Gon
authors: HG
authors: Lee
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D017209:Apoptosis; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced / Q000150:complications / Q000235:genetics*; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology* / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000009:adverse effects; D002453:Cell Cycle; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007545:Isoproterenol / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D002316:Cardiotonic Agents; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; D007545:Isoproterenol