Title:Role of GSK-3 in Cardiac Health: Focusing on Cardiac Remodeling and Heart Failure
Volume: 22
Issue: 13
Author(s): Ubaid Tariq, Shravan K. Uppulapu and Sanjay K. Banerjee*
Affiliation:
- Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, Faridabad-121001,India
Keywords:
GSK-3, Cardiac hypertrophy, Cardiomyocyte proliferation, Cardiac regeneration, Cardiovascular remodelling, ischemic
heart disease.
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.
