Abstract 12723: Suppression of P27kip1 Contributes To Eya4-Mediated Development of Acquired Cardiac Hypertrophy
Introduction: We previously showed that a mutation in the transcription cofactor “Eyes absent” (Eya4) 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 be a negative regulator of the protein kinase inhibitor p27kip1 (p27), a protein shown to regulate hypertrophic responses in the adult cardiomyocyte. This study was aimed to explore the role of Eya4 in angiotensin II (ATII)-induced cardiac hypertrophy.
Methods and results: We constructed a transgenic mouse model with a constitutive myocardial overexpression of HA-tagged Eya4. Wildtype and Eya4 overexpressing mice were challenged with ATII via osmotic minipumps for four weeks to induce cardiac hypertrophy. First analysis of these animals using magnetic resonance imaging to visualize cardiac structures in detail showed that in response to the sustained ATII stimulation, the Eya4 overexpressing mice exhibited a phenotype with significantly increased parameters of hypertrophy. LV free wall diameter as measured in 7T MRI was 1,7±0,2 in Eya4 mice with ATII compared to 1,3±0,2 mm in WT mice with ATII. This was also confirmed by HW/BW ratio, hemodynamic measurements and cell size measurements. Histology also affirmed the results of the MR imaging. Moreover, Eya4 overexpression induced a significant suppression of p27 protein expression which is in agreement with our in vitro data. This confirmed our hypothesis, that Eya4 suppresses p27 expression which facilitates development of myocardial hypertrophy.
Conclusion: In summary, we previously identified 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, thereby augmenting ATII induced cardiac hypertrophy.
- © 2011 by American Heart Association, Inc.