GSK3β Serine 389 Phosphorylation Modulates Cardiomyocyte Hypertrophy and Ischemic Injury.

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.

• Authors: Laura Vainio, Saija Taponen, Sini M Kinnunen, Eveliina Halmetoja, Zoltan Szabo, Tarja Alakoski, Johanna Ulvila, Juhani Junttila, Päivi Lakkisto, Johanna Magga, Risto Kerkelä
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 24 (Dec 18 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34948382 (Publication Type: Journal Article)

Chemical References

• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Gsk3b protein, rat
• Mechanistic Target of Rapamycin Complex 1

Topics

• Animals
• Cardiomegaly (metabolism, pathology)
• Cell Proliferation
• Cell Survival
• Cells, Cultured
• Glycogen Synthase Kinase 3 beta (metabolism)
• Humans
• Male
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Mice
• Mice, Inbred C57BL
• Myocardial Ischemia (metabolism, pathology)
• Myocytes, Cardiac (metabolism, pathology)
• Phosphorylation
• Rats, Sprague-Dawley
• Rats