Fibroblast GSK-3α Promotes Fibrosis via RAF-MEK-ERK Pathway in the Injured Heart.
Animals
Cardiomyopathies
/ metabolism
Collagen
/ metabolism
Extracellular Signal-Regulated MAP Kinases
Fibroblasts
/ metabolism
Fibrosis
Glycogen Synthase Kinase 3
/ metabolism
Glycogen Synthase Kinase 3 beta
/ metabolism
Heart Failure
/ metabolism
MAP Kinase Signaling System
Mice
Mitogen-Activated Protein Kinase Kinases
/ metabolism
Myofibroblasts
/ metabolism
Tamoxifen
/ pharmacology
Transforming Growth Factor beta1
/ metabolism
raf Kinases
cardiovascular diseases
fibroblasts
fibrosis
heart failure
myofibroblasts
Journal
Circulation research
ISSN: 1524-4571
Titre abrégé: Circ Res
Pays: United States
ID NLM: 0047103
Informations de publication
Date de publication:
16 09 2022
16 09 2022
Historique:
pubmed:
3
9
2022
medline:
20
9
2022
entrez:
2
9
2022
Statut:
ppublish
Résumé
Heart failure is the leading cause of mortality, morbidity, and health care expenditures worldwide. Numerous studies have implicated GSK-3 (glycogen synthase kinase-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms seem to play overlapping, unique and even opposing functions in the heart. Previously, we have shown that of the 2 isoforms of GSK-3, cardiac fibroblast GSK-3β acts as a negative regulator of myocardial fibrosis in the ischemic heart. However, the role of cardiac fibroblast-GSK-3α in the pathogenesis of cardiac diseases is completely unknown. To define the role of cardiac fibroblast-GSK-3α in myocardial fibrosis and heart failure, GSK-3α was deleted from fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or Postn-promoter-driven Cre recombinase. Control and GSK-3α KO mice were subjected to cardiac injury and heart parameters were evaluated. The fibroblast kinome mapping was carried out to delineate molecular mechanism followed by in vivo and in vitro analysis. Fibroblast-specific GSK-3α deletion restricted fibrotic remodeling and preserved function of the injured heart. We observed reductions in cell migration, collagen gel contraction, α-SMA protein levels, and expression of ECM genes in TGFβ1-treated KO fibroblasts, indicating that GSK-3α is required for myofibroblast transformation. Surprisingly, GSK-3α deletion did not affect SMAD3 activation, suggesting the profibrotic role of GSK-3α is SMAD3 independent. The molecular studies confirmed decreased ERK signaling in GSK-3α-KO CFs. Conversely, adenovirus-mediated expression of a constitutively active form of GSK-3α (Ad-GSK-3α GSK-3α-mediated MEK-ERK activation is a critical profibrotic signaling circuit in the injured heart, which operates independently of the canonical TGF-β1-SMAD3 pathway. Therefore, strategies to inhibit the GSK-3α-MEK-ERK signaling circuit could prevent adverse fibrosis in diseased hearts.
Sections du résumé
BACKGROUND
Heart failure is the leading cause of mortality, morbidity, and health care expenditures worldwide. Numerous studies have implicated GSK-3 (glycogen synthase kinase-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms seem to play overlapping, unique and even opposing functions in the heart. Previously, we have shown that of the 2 isoforms of GSK-3, cardiac fibroblast GSK-3β acts as a negative regulator of myocardial fibrosis in the ischemic heart. However, the role of cardiac fibroblast-GSK-3α in the pathogenesis of cardiac diseases is completely unknown.
METHODS
To define the role of cardiac fibroblast-GSK-3α in myocardial fibrosis and heart failure, GSK-3α was deleted from fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or Postn-promoter-driven Cre recombinase. Control and GSK-3α KO mice were subjected to cardiac injury and heart parameters were evaluated. The fibroblast kinome mapping was carried out to delineate molecular mechanism followed by in vivo and in vitro analysis.
RESULTS
Fibroblast-specific GSK-3α deletion restricted fibrotic remodeling and preserved function of the injured heart. We observed reductions in cell migration, collagen gel contraction, α-SMA protein levels, and expression of ECM genes in TGFβ1-treated KO fibroblasts, indicating that GSK-3α is required for myofibroblast transformation. Surprisingly, GSK-3α deletion did not affect SMAD3 activation, suggesting the profibrotic role of GSK-3α is SMAD3 independent. The molecular studies confirmed decreased ERK signaling in GSK-3α-KO CFs. Conversely, adenovirus-mediated expression of a constitutively active form of GSK-3α (Ad-GSK-3α
CONCLUSIONS
GSK-3α-mediated MEK-ERK activation is a critical profibrotic signaling circuit in the injured heart, which operates independently of the canonical TGF-β1-SMAD3 pathway. Therefore, strategies to inhibit the GSK-3α-MEK-ERK signaling circuit could prevent adverse fibrosis in diseased hearts.
Identifiants
pubmed: 36052698
doi: 10.1161/CIRCRESAHA.122.321431
pmc: PMC9481711
mid: NIHMS1830626
doi:
Substances chimiques
Transforming Growth Factor beta1
0
Tamoxifen
094ZI81Y45
Collagen
9007-34-5
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
raf Kinases
EC 2.7.11.1
Extracellular Signal-Regulated MAP Kinases
EC 2.7.11.24
Glycogen Synthase Kinase 3
EC 2.7.11.26
glycogen synthase kinase 3 alpha
EC 2.7.11.26
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
620-636Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL133290
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL143074
Pays : United States
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