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Cardiac restricted overexpression of E2F6 alters cell cycle dynamics and results in dilated cardiomyopathy in mice
Author(s) -
Westendorp Bart,
Nader Moni,
Salih Maysoon,
Leenen Frans H,
Tuana Balwant S
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.386.8
Subject(s) - dilated cardiomyopathy , cell cycle , histone , chemistry , biology , microbiology and biotechnology , medicine , endocrinology , biochemistry , apoptosis , heart failure , gene
The E2F transcription factors play a critical role in cell cycle control and developing myocardium. Cardiomyocytes undergo permanent cell cycle arrest shortly after birth and we investigated the role of E2F6, a repressor of E2F‐responsive genes, by generating transgenic (Tg) mice with cardiac‐specific expression of E2F6 driven by the alpha‐myosin heavy chain promoter. Three independent Tg lines with different levels of E2F6 (~3‐, 6‐ and 9‐fold vs wild type) were established, which showed mortality and CHF symptoms in young adults, with increasing severity correlating with E2F6 levels. Echocardiography showed progressive LV dilation and decreasing ejection fractions in Tg mice. E2F6 targeted the nucleus with a profound reduction in phospho‐histone H3 staining but no changes in apoptosis in 4‐day‐old Tg hearts. Increases in the G1/S phase markers cyclin D3, cdk4, p‐Rb were noted while the G2/M marker p‐cdc2 did not change in Tg hearts. Heterochromatin formation was attenuated in Tg hearts, as reflected by reduced methylated histone H3, and histone deacetylase 4 protein. These data suggest that regulated expression of E2F6 is critical for normal cardiac development and function, since overexpression alters chromatin remodeling and cell cycle dynamics, resulting in dilated cardiomyopathy. (Supported by CIHR and HSFO).