Abstract 530: Cardiac Fibroblast GSK-3α Contributes to Ventricular Remodeling and Dysfunction of the Failing Heart

Abstract

Background: Heart failure is the leading cause of mortality, morbidity, and healthcare expenditures 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 isoforms appear to play overlapping, unique and even opposing functions in the heart. Recently our group has identified cardiac fibroblast (CF) GSK-3β as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of CF-GSK-3α in cardiac pathophysiology is poorly understood. Methods and Results: To determine the role of CF-GSK-3α in the pathogenesis of heart failure, GSK -3α was deleted specifically from mouse resident cardiac fibroblast or myofibroblast with tamoxifen-inducible TCF21- or periostin (Postn)- promoter-driven Cre recombinase. At 2 months of age, WT and KO mice were subjected to cardiac injury and heart functions were monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 8 weeks post-injury. In TCF21-KO mice, deletion of GSK-3α from resident cardiac fibroblasts significantly restricted pressure overload-induced adverse cardiac remodeling and improved cardiac function. Consistently, in Postn-KO mice, deletion of GSK-3α from myofibroblasts remarkably reduced LV scar circumference and prevented cardiac dysfunction post-MI. To gain the mechanistic insights of observed GSK-3α mediated fibrotic remodeling, we examined the effect of GSK-3α deletion on myofibroblast transformation and profibrotic TGF-β1-SMAD3 signaling in vitro . WT and GSK-3α KO mouse embryonic fibroblasts (MEFs) were treated with TGF-β1 (10 ng/mL). Indeed, a significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGF-β1 treated GSK-3α KO MEF confirmed that GSK-3α is required for myofibroblast transformation. Surprisingly, GSK-3α deletion had no effect on TGF-β1 induced SMAD3 activation indicating the potential involvement of GSK-3α in eliciting SMAD3 independent profibrotic response. Conclusion: These findings suggest the causal role of CF-GSK3α in the cardiac remodeling of the injured heart that could be a therapeutically targeted for the future clinical applications.