Abstract 270: The Eya4/six1 Signalling Cascade is Activated in Acquired Heart Disease
Rationale: We previously identified a mutation in the human transcriptional cofactor Eya4 as cause of familial dilated cardiomyopathy (DCM). We now provide evidence that the Eya4/Six1 signalling cascade also is crucial in acquired heart disease.
Hypothesis: We hypothesize that the transcriptional complex Eya4/Six1 regulates targets relevant in normal cardiac function. We speculate it, amongst others, regulates expression of p27kip1, a known inhibitor of hypertrophy in adult cardiomyocytes, upon hypertrophic stimuli.
Methods and results: We first examined the correlation of Eya4 and p27 in regards to phosphorylation and cellular distribution in failing and normal human hearts. Immunhistology revealed Eya4 is mainly distributed in the cytoplasm while p27 predominantly resides in the nucleus of healthy myocardial tissue. In sections of failing human hearts, Eya4 accumulated in the perinuclear and nuclear region; nuclear p27 levels were significantly diminished, phosphorylated p27 was evenly distributed in the cytoplasm. In a murine model of MI, IH showed Eya4 translocates in a time-dependent manner. WB analyses for p27 showed an age dependent decrease in p27 protein levels upon MI compared to control littermates. We generated transgenic mice with constitutive myocardial overexpression of Eya4 and E193. As judged by MRI, hemodynamic and morphometric analysis both transgenic mouse models developed cardiac phenotypes compared to age-matched wildtype littermates already under basal conditions in an age dependent manner. p27 expression and downstream factors were also altered in both transgenic lines as a result of Eya4, and accordingly, E193 overexpression. In summary, we provide evidence that the Eya4/Six1 signalling cascade is not only relevant in a rare version of heritable DCM but also in more common forms of acquired heart disease. Eya4/Six1 seems to regulate p27, which was shown to be an important regulator of cardiac physiology in postmitotic cardiomyocytes.
Author Disclosures: T. Williams: None. D. Oppelt: None. P. Nordbeck: None. S. Voll: None. J. Schoenberger: None. O. Ritter: None.
- © 2015 by American Heart Association, Inc.