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Cardiac fibroblast glycogen synthase kinase-3β regulates ventricular remodeling and dysfunction in ischemic heart.
- Source :
-
Circulation [Circulation] 2014 Jul 29; Vol. 130 (5), pp. 419-30. Date of Electronic Publication: 2014 Jun 04. - Publication Year :
- 2014
-
Abstract
- Background: Myocardial infarction-induced remodeling includes chamber dilatation, contractile dysfunction, and fibrosis. Of these, fibrosis is the least understood. After myocardial infarction, activated cardiac fibroblasts deposit extracellular matrix. Current therapies to prevent fibrosis are inadequate, and new molecular targets are needed.<br />Methods and Results: Herein we report that glycogen synthase kinase-3β (GSK-3β) is phosphorylated (inhibited) in fibrotic tissues from ischemic human and mouse heart. Using 2 fibroblast-specific GSK-3β knockout mouse models, we show that deletion of GSK-3β in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction, and excessive scarring in the ischemic heart. Deletion of GSK-3β induces a profibrotic myofibroblast phenotype in isolated cardiac fibroblasts, in post-myocardial infarction hearts, and in mouse embryonic fibroblasts deleted for GSK-3β. Mechanistically, GSK-3β inhibits profibrotic transforming growth factor-β1/SMAD-3 signaling via interactions with SMAD-3. Moreover, deletion of GSK-3β resulted in the significant increase of SMAD-3 transcriptional activity. This pathway is central to the pathology because a small-molecule inhibitor of SMAD-3 largely prevented fibrosis and limited left ventricular remodeling.<br />Conclusions: These studies support targeting GSK-3β in myocardial fibrotic disorders and establish critical roles of cardiac fibroblasts in remodeling and ventricular dysfunction.<br /> (© 2014 American Heart Association, Inc.)
- Subjects :
- Aged
Animals
Enzyme Activation physiology
Extracellular Matrix metabolism
Fibroblasts cytology
Fibrosis metabolism
Fibrosis pathology
Glycogen Synthase Kinase 3 genetics
Glycogen Synthase Kinase 3 beta
Humans
Male
Mice, Knockout
Middle Aged
Myocardial Ischemia pathology
Myocardium cytology
Primary Cell Culture
RNA, Small Interfering genetics
Smad3 Protein metabolism
Ventricular Dysfunction, Left metabolism
Ventricular Dysfunction, Left pathology
Fibroblasts enzymology
Glycogen Synthase Kinase 3 metabolism
Myocardial Ischemia metabolism
Myocardium enzymology
Ventricular Remodeling physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 130
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 24899689
- Full Text :
- https://doi.org/10.1161/CIRCULATIONAHA.113.008364