The GSK-3 family as therapeutic target for myocardial diseases

Abstract

Glycogen synthase kinase-3 (GSK-3) is one of the few signaling molecules that regulate a truly astonishing number of critical intracellular signaling pathways. It has been implicated in several diseases including heart failure, bipolar disorder, diabetes mellitus, Alzheimer 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 used 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 after myocardial infarction 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 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.

Keywords: fibrosis; glycogen synthase kinase-3; heart failure; myocardial infarction.

Figure 1. Signaling cascades regulated by GSK-3 in heart

In response to growth factor binding to their receptors, the PI3K/Akt pathway is activated, leading to inhibition of GSK-3. GSK-3 negatively regulates a host of factors downstream of growth factor signaling, so the consequences of GSK-3 inhibition are activation of these factors including: 1) NF-AT-hypertrophy regulator, 2) glycogen synthase-glycogen synthesis regulator, 3) mTORC1-autophagy and metabolism regulator, 4) D- and E-type cyclins-cell cycle regulator, 3) Myc-metabolism and proliferation regulator. An alternative mechanism to inhibit GSK-3 is mediated by p38. GSK-3β directly binds with SMAD-3 to negatively regulate the profibrotic TGF-β1 signaling. GSK-3 is well known to regulate the canonical Wnt signaling. Phosphorylation of β-catenin by GSK-3 leads to the ubiquitination and degradation of β-catenin by the proteasome, preventing gene expression. In the absence of GSK-3, β-catenin is stabilized, and then translocates to the nucleus leading to gene expression. β-catenin regulates a host of processes from fibrosis to cardiac hypertrophy. GSK-3α regulates AMPK and mTOR, the master regulators of autophagy and metabolism. In the absence of GSK-3α, mTOR is dysregulated leading to impaired autophagy which accelerates the progression of aging. GSK-3α also regulates the β-adrenergic receptor responsiveness and cAMP production via unknown mechanisms. GSK-3α directly interacts and phosphorylates cyclin E1 in cardiomyocytes and its deletion promotes E2F-1 and cyclin E1 recruitment and induces the re-entry of adult cardiomyocytes into the cell cycle. (llustration Credit: Ben Smith).

Figure 2. GSK-3β mediated regulation of pro-fibrotic TGF-β1-SMAD-3 signaling in cardiac fibroblast

GSK-3β exerts dual control on TGF-β1-SMAD-3 signaling by regulating both the C-terminal domain as well as the linker region of SMAD3. In a healthy heart, GSK-3β interacts with, and thereby maintains, the low level activity of SMAD-3. Thus, GSK-3β is a critical regulator of canonical TGF-β1 signaling and its deletion, or inhibition, leads to aberrant hyper-activation of pro-fibrotic TGF-β1-SMAD-3 signaling.