Cardiac Fibroblast Glycogen Synthase Kinase-3β Regulates Ventricular Remodeling and Dysfunction in Ischemic Heart

Abstract

Background Myocardial infarction-induced remodeling includes chamber dilatation, contractile dysfunction, and fibrosis. Of these, fibrosis is the least understood. Following MI, activated cardiac fibroblasts (CFs) deposit extracellular matrix. Current therapies to prevent fibrosis are inadequate and new molecular targets are needed. Methods and Results Herein we report that GSK-3β is phosphorylated (inhibited) in fibrotic tissues from ischemic human and mouse heart. Using two fibroblast-specific GSK-3β knockout mouse models, we show that deletion of GSK-3β in CFs leads to fibrogenesis, left ventricular dysfunction and excessive scarring in the ischemic heart. Deletion of GSK-3β induces a pro-fibrotic myofibroblast phenotype in isolated CFs, in post-MI hearts, and in MEFs deleted for GSK-3β. Mechanistically, GSK-3β inhibits pro-fibrotic TGF-β1-SMAD-3 signaling via interactions with SMAD-3. Moreover, deletion of GSK-3β resulted in the suppression of SMAD-3 transcriptional activity. This pathway is central to the pathology since a small molecule inhibitor of SMAD-3 largely prevented fibrosis and limited LV remodeling. Conclusion These studies support targeting GSK-3β in myocardial fibrotic disorders and establish critical roles of CFs in remodeling and ventricular dysfunction.

Inhibition of glycogen synthase kinase-3β prevents sympathetic hyperinnervation in infarcted rats

“…We showed that there was significantly attenuated cardiac fibrosis in infarcted groups treated with LiCl, SB216763, and the combination of LiCl and SB216763 compared with vehicle. This result contrasted with the findings of Lal et al, 45 showing an increase in the fibrotic response in cardiac fibroblast-conditioned GSK-3b knockout mice after MI. This discrepancy can be explained at least in part, by different affected cells, different levels of GSK-3 inhibition, and different GSK-3 isoforms.…”

Hypoxia-stimulated cardiac fibroblast production of IL-6 promotes myocardial fibrosis via the TGF-β1 signaling pathway

“…Ischemia-associated FBs have a critical influence on myocardial remodeling progression and fibrosis. [1][2][3] Myocardial remodeling is the product of interactions between FBs and adjacent cells, such as CMs, and blood vascular endothelial cells (ECs), although the exact mechanisms remain poorly understood. 4,5 Pleiotropic effects of cardiac FBs are mediated through differentiation to a myofibroblast phenotype and secretion of pro-inflammatory cytokines (eg, IL-6, TGF β, TNFα, and IL-1).…”

Fibroblast deletion of ROCK2 attenuates cardiac hypertrophy, fibrosis, and diastolic dysfunction

“…Fibroblast-specific periostin promoter-driven Cre (Postn-Cre) transgenic mice (mixed background) were provided by Simon J. Conway (Indiana University School of Medicine, Indianapolis, Indiana, USA). Cre recombinase was driven by a 3.9-kb mouse Postn promoter (44)(45)(46). To obtain a fibroblast-specific deletion of the Rock2 gene, (A and B) Representative fluorescent images and quantification of cellular hypertrophy of H9C2 cells stained with sarcomeric α-actinin (green) and DAPI (nuclei, blue).…”