Role of GSK-3 in Cardiac Health: Focusing on Cardiac Remodeling and Heart Failure

Author(s): Ubaid Tariq, Shravan K. Uppulapu, Sanjay K. Banerjee*

Journal Name: Current Drug Targets

Volume 22 , Issue 13 , 2021


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Abstract:

Glycogen synthase kinase 3 (GSK-3) is a ubiquitously expressed serine/threonine kinase and was first identified as a regulator of glycogen synthase enzyme and glucose homeostasis. It regulates cellular processes like cell proliferation, metabolism, apoptosis and development. Recent findings suggest that GSK-3 is required to maintain the normal cardiac homeostasis that regulates cardiac development, proliferation, hypertrophy and fibrosis. GSK-3 is expressed as two isoforms, α and β. The role of GSK-3α and GSK-3β in cardiac biology is well documented. Both isoforms have common as well as isoform-specific functions. Human data also suggests that GSK-3β is downregulated in hypertrophy and heart failure and acts as a negative regulator. Pharmacological inhibition of GSK-3α and GSK-3β leads to endogenous cardiomyocyte proliferation and cardiac regeneration via the upregulation of cell cycle regulators, which results in cell cycle re-entry and DNA synthesis. It was found that cardiac-specific knockout (KO) of GSK-3α retained cardiac function, inhibited cardiovascular remodelling and restricted scar expansion during ischemia. Further, knockout of GSK-3α decreases cardiomyocyte apoptosis and enhances its proliferation. However, GSK-3β KO also results in hypertrophic myopathy due to cardiomyocyte hyper-proliferation. Thus GSK-3 inhibitors are named as a double-edged sword because of their beneficial and off-target effects. This review focuses on the isoform-specific functions of GSK-3 that will help in better understanding the role of GSK-3α and GSK-3β in cardiac biology and pave the way for the development of new isoform-specific GSK-3 modulator for the treatment of ischemic heart disease, cardiac regeneration and heart failure.

Keywords: GSK-3, Cardiac hypertrophy, Cardiomyocyte proliferation, Cardiac regeneration, Cardiovascular remodelling, ischemic heart disease.

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Article Details

VOLUME: 22
ISSUE: 13
Year: 2021
Published on: 23 February, 2021
Page: [1568 - 1576]
Pages: 9
DOI: 10.2174/1389450122666210224105430
Price: $65

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