Abstract P3056: Cardiac Fibroblast GSK-3α Contributes To Chronic Inflammation In The Ischemic Heart

Background: Myocardial Infarction (MI) is the leading cause of death worldwide. Glycogen Synthase Kinase-3 (GSK-3) has been identified as a promising therapeutic target to treat cardiovascular diseases. The GSK-3 family has 2 isoforms, α and β. Previously, our lab has identified cardiac fibroblast (FB) GSK-3β acts as a negative regulator of fibrosis in the ischemic heart. However, the role of FB-GSK-3α in MI-induced adverse cardiac remodeling is not defined. Methods and Results: To determine the role of FB-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 the 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. Serial echocardiographic analysis revealed that FB-GSK-3α KO mice were protected from MI-induced systolic dysfunction and dilative remodeling. To investigate the role of FB-GSK-3α in MI-induced chronic inflammation, hearts were harvested at 4 weeks post-MI, and expression of signature inflammatory genes (TNFα, IL-6, IL-1β) was analyzed by qPCR. Surprisingly, the KO heart displayed remarkably low levels of inflammatory gene expression. To delineate underlying mechanisms, the effect of FB-GSK-3α deletion on the pro-inflammatory Nuclear factor kappa B (NF-κB) pathway was examined in vitro . Western blot analysis confirmed a significant reduction in NF-κB activation in GSK-3α-KO FBs. Importantly, the co-culture experiment demonstrated that the expression of inflammatory genes was downregulated in immune cells when cultured with GSK-3α KO FBs. These results indicate that GSK-3α can modulate immune cell phenotype through FB-immune cell crosstalk. Conclusion: Our findings suggest a critical role of FB-GSK-3α in pathological cardiac remodeling and heart failure that could be therapeutically targeted for future clinical applications.