University of Oulu

Vainio, L., Taponen, S., Kinnunen, S. M., Halmetoja, E., Szabo, Z., Alakoski, T., Ulvila, J., Junttila, J., Lakkisto, P., Magga, J., & Kerkelä, R. (2021). GSK3β Serine 389 Phosphorylation Modulates Cardiomyocyte Hypertrophy and Ischemic Injury. International Journal of Molecular Sciences, 22(24), 13586. https://doi.org/10.3390/ijms222413586

GSK3β serine 389 phosphorylation modulates cardiomyocyte hypertrophy and ischemic injury

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Author: Vainio, Laura1,2; Taponen, Saija1,2; Kinnunen, Sini M.1,3;
Organizations: 1Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu 90220, Finland
2Biocenter Oulu, University of Oulu, Oulu 90220, Finland
3Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland
4Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu 90220, Finland
5Research Unit of Internal Medicine, Division of Cardiology, Oulu University Hospital and University of Oulu, Oulu 90220, Finland
6Unit of Cardiovascular Research, Minerva Institute for Medical Research, Helsinki 00014, Finland
7Department of Clinical Chemistry and Hematology, University of Helsinki and Helsinki University Hospital, Helsinki 00014, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022022220449
Language: English
Published: Multidisciplinary Digital Publishing Institute, 2021
Publish Date: 2022-02-23
Description:

Abstract

Prior studies show that glycogen synthase kinase 3β (GSK3β) contributes to cardiac ischemic injury and cardiac hypertrophy. GSK3β is constitutionally active and phosphorylation of GSK3β at serine 9 (S9) inactivates the kinase and promotes cellular growth. GSK3β is also phosphorylated at serine 389 (S389), but the significance of this phosphorylation in the heart is not known. We analyzed GSK3β S389 phosphorylation in diseased hearts and utilized overexpression of GSK3β carrying ser→ala mutations at S9 (S9A) and S389 (S389A) to study the biological function of constitutively active GSK3β in primary cardiomyocytes. We found that phosphorylation of GSK3β at S389 was increased in left ventricular samples from patients with dilated cardiomyopathy and ischemic cardiomyopathy, and in hearts of mice subjected to thoracic aortic constriction. Overexpression of either GSK3β S9A or S389A reduced the viability of cardiomyocytes subjected to hypoxia–reoxygenation. Overexpression of double GSK3β mutant (S9A/S389A) further reduced cardiomyocyte viability. Determination of protein synthesis showed that overexpression of GSK3β S389A or GSK3β S9A/S389A increased both basal and agonist-induced cardiomyocyte growth. Mechanistically, GSK3β S389A mutation was associated with activation of mTOR complex 1 signaling. In conclusion, our data suggest that phosphorylation of GSK3β at S389 enhances cardiomyocyte survival and protects from cardiomyocyte hypertrophy

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Series: International journal of molecular sciences
ISSN: 1661-6596
ISSN-E: 1422-0067
ISSN-L: 1661-6596
Volume: 22
Issue: 24
Article number: 13586
DOI: 10.3390/ijms222413586
OADOI: https://oadoi.org/10.3390/ijms222413586
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
1182 Biochemistry, cell and molecular biology
Subjects:
Funding: This work was supported by Academy of Finland (grant number 297094 and 333284 to R.K., grant number 268505 to J.M.); Emil Aaltonen Foundation (to R.K.), Finnish Foundation for Cardiovascular Research (to L.V., J.J., J.M., P.L. and R.K.); Sigrid Juselius Foundation (to J.J. and R.K.); and the Jane and Aatos Erkko Foundation (J.J. and R.K.). L.V. was supported by the Ida Montin Foundation, the Aarne Koskelo Foundation, the Orion–Farmos Foundation, and the Finnish–Norwegian Medical Foundation. P.L. was supported by the Finnish Cultural Foundation.
Academy of Finland Grant Number: 297094
333284
268505
Detailed Information: 297094 (Academy of Finland Funding decision)
333284 (Academy of Finland Funding decision)
268505 (Academy of Finland Funding decision)
Copyright information: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)
  https://creativecommons.org/licenses/by/4.0/