title: 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.
authors.affiliation: From the Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., T.F.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.W.). hind.lal@vanderbilt.edu thomas.l.force@vanderbilt.edu.
authors.forename: Hind
authors.initials: H
authors.lastname: Lal
authors.affiliation: From the Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., T.F.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.W.).
authors.forename: Firdos
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: From the Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., T.F.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.W.).
authors.forename: James
authors.initials: J
authors.lastname: Woodgett
authors.affiliation: From the Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., T.F.); and Department of Medical Biophysics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada (J.W.). hind.lal@vanderbilt.edu thomas.l.force@vanderbilt.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000201:enzymology*; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans
chemical_list: D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3
keywords: fibrosis; glycogen synthase kinase-3; heart failure; myocardial infarction