ArticleCirculation research2022
Fibroblast GSK-3α Promotes Fibrosis via RAF-MEK-ERK Pathway in the Injured Heart.
Article in Circulation research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 64 citations in OpenAlex.
- Periostin-CCL3 Feedforward Signaling Loop Promotes Cardiac Fibrosis and Cardiomyocyte Necroptosis in Arrhythmogenic Cardiomyopathy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Exploring the Molecular Mechanisms of SB216763 in the Therapeutic Intervention of Pulmonary Fibrosis Based on Macrophage Functional Plasticity.Fundamental & clinical pharmacology · 2026Article
- MMT: A Potential Mechanism of Myocardial Fibrosis - Regulation of the TGF-β1/Smad3 Pathway and Prospects for Targeted Therapy.Reviews in cardiovascular medicine · 2026Review
- Kinase regulation of miRNA networks in cardiometabolic disease: emerging pathways to precision therapy.Journal of molecular medicine (Berlin, Germany) · 2026Review
- S100A4 Orchestrates Fibroblast Fate to Drive Fibrotic Remodeling.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Iminostilbene, a Carbamazepine Intermediate, Alleviates Myocardial Fibrosis after Myocardial Infarction via Targeting Galectin3.ACS pharmacology & translational science · 2026Article
- Molecular Mechanism of POSTN Mediating M2 Polarization of Kupffer Cells to Promote Hepatic Fibrosis.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Serpine1 Regulates the Enhanced Inhibitory Effect of CHIR99021 Combined with Fibroblast Growth Factor 2 on Myocardial Fibrosis After Myocardial Infarction in Mice.International journal of molecular sciences · 2026Article
- Identification of Biomarkers for Right Ventricular Dysfunction in Idiopathic Dilated Cardiomyopathy Via Urinary Proteomics and Machine Learning.Journal of the American Heart Association · 2026Article
- Meox1 Promotes Cardiac Fibrosis and Pathological Remodeling following Myocardial Infarction through Cthrc1/p-Smad2/3 Signaling.International journal of biological sciences · 2026Article
- Molecular Frameworks for ERK1/2 Inhibition: Lessons from Synthetic and SAR Explorations.ACS omega · 2025Review
- Inhibition of HuR/ELAVL-1 attenuates fibrotic progression in Mdx mice with dilated cardiomyopathy.Cellular and molecular life sciences : CMLS · 2025Article
- Bisecting GlcNAc expression by bone marrow stromal cells modulates TGF-β1-driven macrophage polarization in myeloid leukemias.Haematologica · 2025Article
- Glycogen Synthase Kinase 3 Is Essential for Intestinal Cell Niche and Digestive Function.Biology · 2025Article
- Cardiac fibrosis: from mechanisms and models to medicines.Trends in pharmacological sciences · 2025Review
- Cell type specificity of Hippo-YAP signaling in cardiac development and disease.Journal of molecular and cellular cardiology · 2025Review
- Myocardial fibroblast activation imaging in prediction of cardiac functional improvement of non-ischemic heart failure.International journal of cardiology. Heart & vasculature · 2025Article
- GSK-3α regulates miRNAs associated with transcriptional and metabolic processes in human cardiomyocytes under hypoxia.The Biochemical journal · 2025Article
- PLAC8 as a potential therapeutic target for myocardial infarction: unraveling the molecular mechanisms.Journal of physiology and biochemistry · 2025Article
- MAPK, PI3K/Akt Pathways, and GSK-3β Activity in Severe Acute Heart Failure in Intensive Care Patients: An Updated Review.Journal of cardiovascular development and disease · 2025Review
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Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
Abstract
backgroundHeart 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.
methodsTo 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.
resultsFibroblast-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
conclusionsGSK-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.
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