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

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. 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 the endogenous cardiomyocyte proliferation and cardiac regeneration by inducing 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 about the role of GSK-3α and GSK-3β in cardiac biology and pave a way for the development of new isoform specific GSK-3 modulator for the treatment of ischemic heart disease, cardiac regeneration and heart failure.

Air Pollutants and Mortality Risk in Patients with Aortic Dissection: Evidence from a Clinical Cohort, Single-Cell Sequencing, and Proteomics

“…25,26 In addition, as a point of convergence for the host inflammatory response, GSK-3 has been associated with cardiovascular injury and related diseases, such as cardiac remodeling, cardiomyocyte proliferation, ischemic heart disease, and heart failure. 27,28 More recently, GSK-3β activation has been shown to be involved in aorticdissecting aneurysms, which supports our potential mechanism that GSK-3β may play an important role. 29 Future studies involving molecular biology experiments and animal models are warranted to verify and further explore the detailed mechanisms.…”

“…Moreover, GSK-3β, which is involved in the IL-17 pathway, was found to increase, as judged by both single-cell sequencing and proteomics, and may play an important role. It has been shown that IL-17 promotes inflammation by acting via a GSK-3β-dependent pathway. , In addition, as a point of convergence for the host inflammatory response, GSK-3 has been associated with cardiovascular injury and related diseases, such as cardiac remodeling, cardiomyocyte proliferation, ischemic heart disease, and heart failure. , More recently, GSK-3β activation has been shown to be involved in aortic-dissecting aneurysms, which supports our potential mechanism that GSK-3β may play an important role . Future studies involving molecular biology experiments and animal models are warranted to verify and further explore the detailed mechanisms.…”

Optimal mechanical stretch promotes TSP-1 expression through Akt and GSK-3β/β-catenin signaling pathways in keloid formation.

“…GSK-3β is a ubiquitous serinethreonine kinase that was initially identi ed as an enzyme responsible for regulating glycogen metabolism [22]. Human data suggests that GSK-3β is downregulated in hypertrophic cardiomyopathy and heart failure and functions as a negative regulator [23]. Cheon et al demonstrated that growth factors such as TGF-β could elevate the level of β-catenin by inhibiting GSK-3β activity and prolong the proliferative phase of wound healing, resulting in a scar, during the wound healing process [24].…”

The role of deubiquitinases in cardiac disease

“… 43 ). In a variety of rodent models of cardiac hypertrophy, the specific overexpression of GSK-3 β in myocardium could significantly alleviate myocardial hypertrophy and fibrosis by reducing the nuclear localization of NFAT (Refs 44 , 45 ). The phosphorylation of GSK-3 β is bidirectional.…”