Abstract 15697: Dyrk2 Coordinates Repressor Function of GSK-3β on Protein Synthesis in Cardiac Myocytes
Introduction: A prerequisite of hypertrophic response of the myocardium is an increase in protein synthesis. A central regulator of translation initiation is eIF2B, the Guanine Nucleotide Exchange Factor of eIF2.
Hypothesis: We assessed the hypothesis that regulation of protein synthesis via eIF2Bε is essential to cardiac hypertrophic response in vivo.
Methods: Two novel transgenic mouse lines were generated with cardiac restricted overexpression of eIF2Bε or its mutant eIF2Bε-eIFS535A which cannot be inactivated by phosporylation through GSK-3β. Both transgenes are regulated by the cardiac specific α-MHC promoter. The cardiac phenotype was assessed by invasive pressure volume measurements, echocardiography as well as histopathological and biochemical examinations.
Results: (1) Under baseline conditions eIF2Bε transgenic mice showed no difference in cardiac phenotype compared to wildtype, whereas in the mutant eIF2Bε-S535A an increase in heart weight/tibia length (7.5±0.4 mg/mm vs. 6.2±0.2 mg/mm, p=0.01) and cardiac myocyte cross sectional area (13004±569 vs. 10885±425 AU, p<0.01) was observed. (2) Cardiac overexpression of the eIF2Bε transgene was counteracted by activation of DYRK2 which primes the inhibitory action of GSK-3β on eIF2Bε, while DYRK1 or GSK-3β itself were not activated. (3) In non-transgenic mice after 48h of isoproterenol-stimulation or aortic banding eIF2Bε is increased and DYRK2 is concomitantly decreased indicating a coordinated response pattern following pathologic injury. (4) The in vivo findings could be confirmed in vitro by siRNA mediated Knockdown of eIF2Bε in cultured cardiomyocytes which resulted in a consecutively decreased protein expression of DYRK2.
Conclusion: The interaction of GSK-3β and its priming kinase DYRK2 regulate the activity of eIF2Bε in cardiac myocytes. Our work supports efforts to target DYRK2 as a therapeutic option in myocardial growth.
- © 2010 by American Heart Association, Inc.