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Cardiac fibroblast glycogen synthase kinase-3β regulates ventricular remodeling and dysfunction in ischemic heart

Hind Lal1, Firdos Ahmad1, Jibin Zhou1

  • 1From the Center for Translational Medicine (H.L., F.A., J.Z., J.E.U., R.J.V., Y.G., E.G., T.F.), Department of Clinical Sciences (D.Y.), and Section of Cardiology (E.J.T., T.F.), Temple University School of Medicine, Philadelphia, PA; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (J.W.); and Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (H.L., F.A., Y.G., T.F.).

Circulation
|June 6, 2014
PubMed

Insights

Glycogen synthase kinase-3β (GSK-3β) inhibition promotes cardiac fibrosis by activating myofibroblasts and TGF-β1/SMAD-3 signaling. Targeting GSK-3β may treat myocardial fibrotic disorders.

Area of Science:

  • Cardiovascular Biology
  • Fibrosis Research
  • Molecular Cardiology

Background:

  • Myocardial infarction (MI) causes cardiac remodeling, including fibrosis, which is poorly understood.
  • Current anti-fibrosis therapies are insufficient, necessitating novel molecular targets.
  • Activated cardiac fibroblasts deposit extracellular matrix post-MI, contributing to fibrosis.

Purpose of the Study:

  • To investigate the role of glycogen synthase kinase-3β (GSK-3β) in myocardial fibrosis.
  • To identify GSK-3β as a potential therapeutic target for preventing cardiac fibrosis.

Main Methods:

  • Generated fibroblast-specific GSK-3β knockout mouse models.
  • Analyzed fibrotic tissues from human and mouse hearts post-MI.
  • Investigated GSK-3β's interaction with transforming growth factor-β1/SMAD-3 signaling.
  • Utilized a small-molecule inhibitor of SMAD-3.

Main Results:

  • GSK-3β was found to be phosphorylated (inhibited) in fibrotic heart tissues.
  • Deletion of GSK-3β in cardiac fibroblasts induced a profibrotic myofibroblast phenotype.
  • GSK-3β directly inhibits SMAD-3 transcriptional activity, a key profibrotic pathway.
  • Inhibition of SMAD-3 largely prevented fibrosis and limited left ventricular remodeling post-MI.

Conclusions:

  • GSK-3β plays a critical inhibitory role in cardiac fibroblast activation and fibrosis.
  • Targeting GSK-3β is a promising therapeutic strategy for myocardial fibrotic disorders.
  • Cardiac fibroblasts are key players in post-MI remodeling and ventricular dysfunction.
Abstract

Keywords:
fibroblastsfibrosisglycogen synthase kinase 3 betahypertrophymyocardial infarction

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