title: Targeting GSK-3 family members in the heart: a very sharp double-edged sword.
abstract: The GSK-3 family of serine/threonine kinases, which is comprised of two isoforms (α and β), was initially identified as a negative regulator of glycogen synthase, the rate limiting enzyme of glycogen synthesis [1,2]. In the 30 years since its initial discovery, the family has been reported to regulate a host of additional cellular processes and, consequently, disease states such as bipolar disorders, diabetes, inflammatory diseases, cancer, and neurodegenerative diseases including Alzheimer's Disease and Parkinson's Disease [3,4]. As a result, there has been intense interest on the part of the pharmaceutical industry in developing small molecule antagonists of GSK-3. Herein, we will review the roles played by GSK-3s in the heart, focusing primarily on recent studies that have employed global and tissue-specific gene deletion. We will highlight roles in various pathologic processes, including pressure overload and ischemic injury, focusing on some striking isoform-specific effects of the family. Due to space limitations and/or the relatively limited data in gene-targeted mice, we will not be addressing the family's roles in ischemic pre-conditioning or its many interactions with various pro- and anti-apoptotic factors. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."
authors.affiliation: Center for Translational Medicine and Cardiology Division, Thomas Jefferson University Hospital, Philadelphia, PA, USA. hui.cheng@jefferson.edu
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.forename: James
authors.initials: J
authors.lastname: Woodgett
authors.forename: Mia
authors.initials: M
authors.lastname: Maamari
authors.forename: Thomas
authors.initials: T
authors.lastname: Force
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000502:physiology; D017353:Gene Deletion; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D058990:Molecular Targeted Therapy; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D057170:Translational Research, Biomedical; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3