The GSK-3 Family as Therapeutic Target for Myocardial Diseases

Abstract

GSK-3 is one of the very few signaling molecules that regulate a truly astonishing number of critical intracellular signaling pathways. It has been implicated in a number of diseases including heart failure, bipolar disorder, diabetes, Alzheimer’s disease, aging, inflammation and cancer. Furthermore, a recent clinical trial has validated the feasibility of targeting GSK-3 with small molecule inhibitors for human diseases. In the current review we will focus on its expanding role in the heart, concentrating primarily on recent studies that have employed cardiomyocyte- and fibroblast-specific conditional gene deletion in mouse models. We will highlight the role of the GSK-3 isoforms in various pathological conditions including myocardial aging, ischemic injury, myocardial fibrosis and cardiomyocyte proliferation. We will discuss our recent findings that deletion of GSK-3α specifically in cardiomyocytes attenuates ventricular remodeling and cardiac dysfunction post-MI by limiting scar expansion and promoting cardiomyocyte proliferation. The recent emergence of GSK-3β as a regulator of myocardial fibrosis will also be discussed. We will review our very recent findings that specific deletion of GSK-3β in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction and excessive scarring in the ischemic heart. Finally, we will examine the underlying mechanisms that drive the aberrant myocardial fibrosis in the models in which GSK-3β is specifically deleted in cardiac fibroblasts. We will summarize these recent results and offer explanations, whenever possible, and hypotheses when not. For these studies we will rely heavily on our models and those of others to reconcile some of the apparent inconsistencies in the literature.

Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy

“…Indeed, optimism for developing GSK-3 inhibitors for clinical use remains high for treatment of a variety of severe pathological conditions including progressive central nervous system disorders, cancer, metabolic disorders and even ischemic cardiac injury. 5,19–21 Current clinical trials are testing GSK-3 inhibitors for chronic treatment of patients with Alzheimer’s disease and supranuclear palsy. 19,20 Although safety was achieved in two Phase-1 clinical trials, our current data provides a cautionary note for the potential consequences of chronic pharmacological GSK-3 inhibition in the heart.…”

GSK-3β heterozygous knockout is cardioprotective in a knockin mouse model of familial dilated cardiomyopathy

“…Although the name is derived from its role in glycogen metabolism, recent studies have revealed that GSK-3 is a multifunctional enzyme regulating many biological processes in the heart, including gene expression, hypertrophy, development, proliferation, fibrosis, and apoptosis, being a therapeutic target for myocardial diseases (4,17). Knockout (KO) of GSK-3␤ in the mouse whole body is embryonic lethal due to severe liver degeneration and obliteration of the ventricular cavity via cardiomyocyte hyperproliferation (14).…”

Atorvastatin Protects Myocardium Against Ischemia-Reperfusion Injury Through Inhibiting miR-199a-5p

“…Apoptosis of cardiomyocytes is known to be an important mechanism of I/R injury [3,4,5]. Accumulating evidence has shown that apoptosis of cardiomyocytes is suppressed by glycogen synthase kinase-3β (GSK-3β) [6,7,8]. Therefore manipulation of GSK-3β is a promising strategy for myocardial protection in I/R injury.…”