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• W2320186592 abstract "Introduction: A precise role for Eya4 in the myocardium has not yet been identified. E193, a truncating mutation in the transcription cofactor, leads to late-onset DCM. We provide evidence Eya4, together with Six1, plays a critical role in maintaining cardiac morpho- and physiology by, at least in part, suppressing p27kip1 (p27), a cyclin dependent kinase inhibitor shown to regulate hypertrophic responses in adult cardiomyocytes. This study was aimed to gain better insight into the role of Eya4 in context with p27 and the development of hypertrophy in vivo. Methods and results: We generated transgenic mice (TG) with constitutive cardiac-specific overexpression of Eya4 and E193 to elucidate the in vivo function of Eya4 in cardiac physiology. Long-term experiments showed both TG models developed cardiac phenotypes already under baseline conditions: Eya4 TG developed hypertrophy, whereas E193 animals presented with DCM in an age dependent manner as seen in human patients carrying the E193-mutation. In a second experimental setting, 12 week old WT and TG mice were subjected to pressure overload via transverse aortic constriction (TAC) for four weeks. MRI to visualize cardiac structures and morphology in detail showed Eya4 TG mice developed a phenotype with significantly increased parameters of hypertrophy in response to TAC compared to control littermates. LV free wall diameter as measured in 7T MRI was 1.8±0.2mm in Eya4 mice with TAC compared to 1.5±0.1 mm in WT/TAC, whereas E193 overexpression attenuated development of hypertrophy uponTAC (1.0±0.1 mm in E193/TAC). This was also confirmed by determining hemodynamic parameters, an increase in HW/BW ratio, and cell size measurements. Histology also affirmed the results of the MRI. Moreover, Eya4 overexpression induced a significant suppression of p27 protein expression, while E193 TG mice, even upon TAC, showed slightly elevated p27 levels compared to WT mice, which is in agreement with our in vitro data. This confirmed our hypothesis, whereupon Eya4 suppresses p27 expression which then in turn induces the development of myocardial hypertrophy. Westernblot analysis and kinase activity assays suggest CK2 and HDAC, critical mediators of hypertrophy, as downstream targets in the Eya4-Six1/p27 signalling cascade. Conclusion: In summary, we previously identified a mutation in Eya4 to disturb cardiac physiology. We now provide evidence Eya4 is also involved in forms of acquired heart disease. The Eya4/Six1 complex suppresses p27, thereby activating the CK2-HDAC cascade which in turn augments pressure overload-induced cardiac hypertrophy." @default.
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• W2320186592 date "2013-08-02" @default.
• W2320186592 modified "2023-09-23" @default.
• W2320186592 title "Eyes absent homolog 4 regulates p27Kip1 and aggravates pressure overload-induced adverse cardiac remodeling" @default.
• W2320186592 doi "https://doi.org/10.1093/eurheartj/eht309.p3245" @default.
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