DYRK2 Negatively Regulates Cardiomyocyte Growth by Mediating Repressor Function of GSK-3β on eIF2Bε

Background: A prerequisite of hypertrophic response of the myocardium is an increase in protein synthesis. A central regulator of translation initiation is Eukaryotic initiation factor 2B (eIF2B). Here we assessed the hypothesis that regulation of protein synthesis via eIF2B epsilon is essential to cardiac hypertrophic response in vivo. Methods: Two transgenic mouse lines were generated with cardiac restricted overexpression of eIF2Be or its mutant eIF2B epsilon-eIFS(535)A, which cannot be inactivated by phosphorylation through GSK-3 beta. Results: (1) Under baseline conditions eIF2B epsilon transgenic mice showed no difference in cardiac phenotype compared to wild type, whereas in the mutant eIF2B epsilon-S(535)A an increase in LV/tibia length (7.5 +/- 0.4 mg/mm vs. 6.2 +/- 0.2 mg/mm, p < 0.001) and cardiomyocyte cross sectional area (13004 +/- 570 vs. 10843 +/- 347 RU, p < 0.01) was observed. (2) Cardiac overexpression of eIF2B epsilon did not change the response of the heart to pathologic stress induced by chronic isoproterenol treatment. (3) Cardiac overexpression of the eIF2B epsilon transgene was followed by overexpression of DYRK2 which is known to prime the inhibitory action of GSK-3b on eIF2B epsilon, while DYRK1A and GSK-3 beta itself were not increased. (4) In C57BL/6 mice after 48 h of isoproterenol-stimulation or aortic banding, eIF2B epsilon was increased and DYRK2 was concomitantly decreased. (5) In line with these in vivo findings, siRNA knockdown of DYRK2 in cultured cardiomyocytes resulted in decreased levels of p(S535)eIF2B epsilon, (6) whereas adenoviral induced overexpression of DYRK2 was accompanied by clearly increased phosphorylation of eIF2B epsilon, indicating a coordinated response pattern (7) Adenoviral induced overexpression of DYRK2 leads to significantly reduced cardiomyocyte size and diminishes hypertrophic response to adrenergic stimulation. Conclusions: The interaction of GSK-3 beta and its priming kinase DYRK2 regulate the activity of eIF2B epsilon in cardiac myocytes. DYRK2 is a novel negative regulator of cardiomyocyte growth. DYRK2 could serve as a therapeutic option to regulate myocardial growth.