The Transcription Cofactor Eya4 Mediates the Development of Acquired Cardiac Hypertrophy

Introduction: Eyes absent 4 (Eya4) is a transcription cofactor involved in a number of cellular and developmental processes. We have previously shown that a mutation in Eya4 (E193) leads to late-onset familial dilated cardiomyopathy and heart failure. A precise role for Eya4 in the myocardium has not yet been identified. It appears to regulate the cyclin dependent kinase inhibitor p27 kip1 (p27), a protein shown to regulate hypertrophic responses in the adult cardiomyocyte. This study was aimed to explore the role of Eya4 in induced cardiac hypertrophy. Methods and results: We generated transgenic mice with cardiac-specific overexpression of HA-tagged Eya4 or E193 to elucidate the function of these proteins in the development of heart failure in vivo . These and wildtype littermates were challenged with angiotensin II (ATII) or subjected to transaortic constriction (TAC). Magnetic resonance imaging to visualize cardiac structures in detail showed that in response to sustained ATII stimulation and TAC, Eya4 mice exhibited a phenotype with significantly increased parameters of hypertrophy compared to WT and E193 overexpressing animals as judged by increases in heart weight and LV free wall diameter, cross-sectional cell surface areas and fibrosis. MRI also showed mild cardiac hypertrophy in Eya4 transgenic mice already under baseline conditions in an age dependent fashion. Moreover, Eya4 overexpression induced a significant suppression of p27 protein expression and resulted in increased levels of phosphorylated histone deacetylase 2 (HDAC2). E193 overexpression induced age dependent wall thinning and ventricular dilation under baseline conditions with no obvious structural or functional defects. ATII or TAC induced significant changes in HW/BW ratio, IVS, fibrosis, hemodynamic and cell size measurements, albeit to a lesser extent than seen with Eya4 mice. p27 expression and pHDAC2 levels were only slightly altered. Conclusion: In summary, we have demonstrated a mutation in Eya4 to disturb cardiac physiology. We now provide evidence that Eya4 is also involved in forms of acquired heart disease. It seems to suppress p27, which leads to phosphorylation and activation of HDAC2 and results in the development of cardiac hypertrophy.