Abstract EC106: Cardiac Fibroblast GSK-3α Aggravates Ischemic Cardiac Injury By Promoting Fibrosis, Inflammation, And Impairing Angiogenesis

Abstract

Background: Myocardial Infarction (MI) is the leading cause of death worldwide. Numerous studies from our lab and others have implicated Glycogen Synthase Kinase-3 (GSK-3) as 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 has identified that cardiac fibroblast (CF) GSK-3β acts as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of CF-GSK-3α in MI-induced adverse cardiac remodeling is not defined. Methods and Results: To determine the role of CF-GSK-3α in MI-induced adverse cardiac remodeling, GSK-3α was deleted specifically in the activated fibroblast/myofibroblast using tamoxifen (TAM)-inducible Periostin promoter-driven Cre recombinase system. At 12 weeks of age, mice were fed with TAM diet. After 1 week of TAM treatment, control (GSK-3α fl/fl Cre -/- ) and KO (GSK-3α fl/fl Cre +/- ) mice were subjected to permanent LAD ligation (MI) surgery. Echocardiographic analysis revealed that control mice developed severe systolic dysfunction and dilative cardiac remodeling post-MI. These MI-induced pathologies were remarkably prevented by myofibroblast-specific GSK-3α deletion. To further confirm the role of CF-GSK-3α in processes contributing to cardiac remodeling, 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-1β), fibrosis (COL1A1, COL3A1, COMP), and angiogenesis (VEGFR2, CD31, HIF-1α). As expected, ischemic injury induced the expression of inflammation and fibrosis-related genes in the control group. In contrast, CF-GSK-3α KO hearts did not display any of these hallmarks. Another critical feature of adverse cardiac remodeling is impaired angiogenesis. Indeed, the CF-GSK-3α KO hearts were protected from MI-induced reduction in angiogenesis-related genes. Taken together, our findings support a driving role of CF-GSK-3α in MI-induced adverse cardiac remodeling. Conclusion: Our findings suggest a critical role of CF-GSK-3α in pathological cardiac remodeling and heart failure that could be therapeutically targeted for future clinical applications.