Cardiac fibroblast GSK-3α aggravates ischemic cardiac injury by promoting fibrosis, inflammation, and impairing angiogenesis.

Myocardial infarction (MI) is the leading cause of death worldwide. Glycogen synthase kinase-3 (GSK-3) has been considered to be a promising therapeutic target for cardiovascular diseases. GSK-3 is a family of ubiquitously expressed serine/threonine kinases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Previously, our group identified that cardiac fibroblast (FB) GSK-3ß acts as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of FB-GSK-3α in MI pathology is not defined. To determine the role of FB-GSK-3α in MI-induced adverse cardiac remodeling, GSK-3α was deleted specifically in the residential fibroblast or myofibroblast (MyoFB) using tamoxifen (TAM) inducible Tcf21 or Periostin (Postn) promoter-driven Cre recombinase, respectively. Echocardiographic analysis revealed that FB- or MyoFB-specific GSK-3α deletion prevented the development of dilative remodeling and cardiac dysfunction. Morphometrics and histology studies confirmed improvement in capillary density and a remarkable reduction in hypertrophy and fibrosis in the KO group. We harvested the hearts at 4 weeks post-MI and analyzed signature genes of adverse remodeling. Specifically, qPCR analysis was performed to examine the gene panels of inflammation (TNFα, IL-6, IL-1ß), fibrosis (COL1A1, COL3A1, COMP, Fibronectin-1, Latent TGF-ß binding protein 2), and hypertrophy (ANP, BNP, MYH7). These molecular markers were essentially normalized due to FB-specific GSK-3α deletion. Further molecular studies confirmed that FB-GSK-3α could regulate NF-kB activation and expression of angiogenesis-related proteins. Our findings suggest that FB-GSK-3α plays a critical role in the pathological cardiac remodeling of ischemic hearts, therefore, it could be therapeutically targeted.

GSK-3 at the heart of cardiometabolic diseases: Isoform-specific targeting is critical to therapeutic benefit.

Glycogen synthase kinase-3 (GSK-3) is a family of serine/threonine kinases. The GSK-3 family has 2 isoforms, GSK-3α and GSK-3ß. The GSK-3 isoforms have been shown to play overlapping as well as isoform-specific-unique roles in both, organ homeostasis and the pathogenesis of multiple diseases. In the present review, we will particularly focus on expanding the isoform-specific role of GSK-3 in the pathophysiology of cardiometabolic disorders. We will highlight recent data from our lab that demonstrated the critical role of cardiac fibroblast (CF) GSK-3α in promoting injury-induced myofibroblast transformation, adverse fibrotic remodeling, and deterioration of cardiac function. We will also discuss studies that found the exact opposite role of CF-GSK-3ß in cardiac fibrosis. We will review emerging studies with inducible cardiomyocyte (CM)-specific as well as global isoform-specific GSK-3 KOs that demonstrated inhibition of both GSK-3 isoforms provides benefits against obesity-associated cardiometabolic pathologies. The underlying molecular interactions and crosstalk among GSK-3 and other signaling pathways will be discussed. We will briefly review the specificity and limitations of the available small molecule inhibitors targeting GSK-3 and their potential applications to treat metabolic disorders. Finally, we will summarize these findings and offer our perspective on envisioning GSK-3 as a therapeutic target for the management of cardiometabolic diseases.