DYRK2 Negatively Regulates Cardiomyocyte Growth by Mediating Repressor Function of GSK-3b on eIF2Be

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 eIF2Be is essential to cardiac hypertrophic response in vivo. Methods: Two transgenic mouse lines were generated with cardiac restricted overexpression of eIF2Be or its mutant eIF2Be-eIFS535A, which cannot be inactivated by phosphorylation through GSK-3b. Results: (1) Under baseline conditions eIF2Be transgenic mice showed no difference in cardiac phenotype compared to wild type, whereas in the mutant eIF2Be-S535A an increase in LV/tibia length (7.560.4 mg/mm vs. 6.260.2 mg/mm, p,0.001) and cardiomyocyte cross sectional area (130046570 vs. 108436347 RU, p,0.01) was observed. (2) Cardiac overexpression of eIF2Be did not change the response of the heart to pathologic stress induced by chronic isoproterenol treatment. (3) Cardiac overexpression of the eIF2Be transgene was followed by overexpression of DYRK2 which is known to prime the inhibitory action of GSK-3b on eIF2Be, while DYRK1A and GSK-3b itself were not increased. (4) In C57BL/6 mice after 48 h of isoproterenol-stimulation or aortic banding, eIF2Be 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)-eIF2Be, (6) whereas adenoviral induced overexpression of DYRK2 was accompanied by clearly increased phosphorylation o