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

• Published in: PloS one Vol. 8; no. 9; p. e70848
• Main Authors: Weiss, Celine S, Ochs, Marco M, Hagenmueller, Marco, Streit, Marcus R, Malekar, Pratima, Riffel, Johannes H, Buss, Sebastian J, Weiss, Karl H, Sadoshima, Junichi, Katus, Hugo A, Hardt, Stefan E
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04-09-2013; Public Library of Science (PLoS)
• Subjects: Animals; Aorta; Banding; Cardiomyocytes; Cells, Cultured; Dyrk Kinases; Echocardiography; Eukaryotic Initiation Factor-2B - genetics; Eukaryotic Initiation Factor-2B - metabolism; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Growth factors; Heart; Heart diseases; Heart failure; Hypertrophy, Left Ventricular - genetics; Hypertrophy, Left Ventricular - metabolism; Immunoprecipitation; In vivo methods and tests; Initiation factor eIF-2; Internal medicine; Isoproterenol; Kinases; Male; Medicine; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardium; Myocytes; Myocytes, Cardiac - metabolism; Phosphorylation; Physiology; Priming; Protein biosynthesis; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein synthesis; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proteins; Real-Time Polymerase Chain Reaction; Regulation; RNA, Small Interfering - genetics; Rodents; siRNA; Stimulation; Studies; Tibia; Transgenic mice; Translation initiation; United States > US; New Jersey
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0070848

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 eIF2Bε is essential to cardiac hypertrophic response in vivo.
Two transgenic mouse lines were generated with cardiac restricted overexpression of eIF2Bε or its mutant eIF2Bε-eIFS(535)A, which cannot be inactivated by phosphorylation through GSK-3β.
(1) Under baseline conditions eIF2Bε transgenic mice showed no difference in cardiac phenotype compared to wild type, whereas in the mutant eIF2Bε-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 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.
The 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.