DYRK2 negatively regulates cardiomyocyte growth by mediating repressor function of GSK-3β on eIF2Bε.

Celine S Weiss,Stefan E Hardt,Marco Hagenmueller,Sebastian J Buss,Marcus R Streit,Pratima Malekar,Johannes H Riffel,Marco M Ochs,Hugo A Katus,Junichi Sadoshima,Karl H Weiss,Rossella Rota

doi:10.1371/journal.pone.0070848

Abstract

BackgroundA 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 eIF2Bε is essential to cardiac hypertrophic response in vivo.MethodsTwo transgenic mouse lines were generated with cardiac restricted overexpression of eIF2Bε or its mutant eIF2Bε-eIFS535A, which cannot be inactivated by phosphorylation through GSK-3β.Results(1) Under baseline conditions eIF2Bε transgenic mice showed no difference in cardiac phenotype compared to wild type, whereas in the mutant eIF2Bε-S535A 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 eIF2Bε did not change the response of the heart to pathologic stress induced by chronic isoproterenol treatment. (3) Cardiac overexpression of the eIF2Bε transgene was followed by overexpression of DYRK2 which is known to prime the inhibitory action of GSK-3β on eIF2Bε, while DYRK1A and GSK-3β itself were not increased. (4) In C57BL/6 mice after 48 h of isoproterenol-stimulation or aortic banding, eIF2Bε 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)- eIF2Bε, (6) whereas adenoviral induced overexpression of DYRK2 was accompanied by clearly increased phosphorylation of eIF2Bε, indicating a coordinated response pattern (7) Adenoviral induced overexpression of DYRK2 leads to significantly reduced cardiomyocyte size and diminishes hypertrophic response to adrenergic stimulation.ConclusionsThe interaction of GSK-3β and its priming kinase DYRK2 regulate the activity of eIF2Bε in cardiac myocytes. DYRK2 is a novel negative regulator of cardiomyocyte growth. DYRK2 could serve as a therapeutic option to regulate myocardial growth.

Highlights

Left ventricular hypertrophy (LVH) is an important risk factor for ischemia, arrhythmia and sudden death, independent of the underlying hypertrophic stimulus [1]
(5) In line with these in vivo findings, siRNA knockdown of Dual specificity tyrosine-phosphorylation-regulated kinase 2 (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 of eIF2Be, indicating a coordinated response pattern (7) Adenoviral induced overexpression of DYRK2 leads to significantly reduced cardiomyocyte size and diminishes hypertrophic response to adrenergic stimulation
The interaction of Glycogen synthase kinase 3b (GSK-3b) and its priming kinase DYRK2 regulate the activity of eIF2Be in cardiac myocytes

Summary

Introduction

Left ventricular hypertrophy (LVH) is an important risk factor for ischemia, arrhythmia and sudden death, independent of the underlying hypertrophic stimulus [1]. EIF2B is a guanine nucleotide exchange factor which mediates the exchange of GDP bound to translation initiation factor eIF2 for GTP. We have previously shown that the guanine nucleotide exchange factor 2B is one of these crucial regulators of protein synthesis and cardiomyocyte growth in vitro [3]. This exchange process is a key regulatory step for the control of translation initiation in all eukaryotic organisms and increases thereby protein synthesis. We assessed the hypothesis that regulation of protein synthesis via eIF2Be is essential to cardiac hypertrophic response in vivo

Methods

Results

Conclusion