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

[ Vol. 22 , Issue. 13 ]

Author(s):

Ubaid Tariq, Shravan K. Uppulapu and Sanjay K. Banerjee*   Pages 1568 - 1576 ( 9 )

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.

Affiliation:

Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, Faridabad-121001, Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati- 781101, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, Faridabad-121001

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