ArticleJournal of molecular and cellular cardiology2022
Glutamine uptake and catabolism is required for myofibroblast formation and persistence.
Article in Journal of molecular and cellular cardiology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 38 citations in OpenAlex.
- Bidirectional metabolic-vascular feedback loops in heart failure: From myocardial energetics to multisystem cardiometabolic crosstalk.iScience · 2026Review
- Glutamine Metabolism: a Metabolic Hub Linking Vascular Remodeling and Plaque Stability in Atherosclerosis.Current atherosclerosis reports · 2026Review
- Fueling fibrosis: BCAT1 links branched-chain amino acid metabolism to collagen production.The Journal of clinical investigation · 2026Article
- Glutamine Metabolism in Cardiac Hypertrophy.Reviews in cardiovascular medicine · 2026Review
- Stretch strain shifts optic nerve head astrocyte metabolism to enrich α-ketoglutarate and the pentose phosphate pathway.Scientific reports · 2026Article
- Immunometabolism in Cardiac Remodeling: Mechanisms and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- MLKL Deficiency Stabilizes RIP3 and Aggravates Myocardial Injury by Promoting Apoptosis and Pyroptosis.Current issues in molecular biology · 2026Article
- GPT2-mediated Glutamate to α-Ketoglutaric Acid Conversion in Cardiac Fibroblast Promotes Fibrosis.JACC. Basic to translational science · 2026Article
- Roles of Exosome-Derived Noncoding RNA in Fibrosis.Molecules and cells · 2026Review
- The Glutamine-α-Ketoglutarate Metabolic Axis Controls Vascular Smooth Muscle Cell Function.Cells · 2026Article
- Hypoxia-driven crosstalk among cardiac fibroblasts, macrophages, and endothelial cells in cardiac fibrosis.Frontiers in cell and developmental biology · 2026Review
- The role of glutamine metabolism in the pathogenesis of idiopathic pulmonary fibrosis and its therapeutic potential.Frontiers in oncology · 2026Review
- Metabolic reprogramming in cardiac fibrosis: mechanisms, crosstalk, and therapeutic interventions.Frontiers in physiology · 2026Review
- Inhibition of HuR/ELAVL-1 attenuates fibrotic progression in Mdx mice with dilated cardiomyopathy.Cellular and molecular life sciences : CMLS · 2025Article
- The addition of alpha-ketoglutarate to NT-proBNP improves the prediction of long-term all-cause mortality in acute heart failure patients.Annals of medicine · 2025Article
- Cardiac intermediary metabolism in heart failure: substrate use, signalling roles and therapeutic targets.Nature reviews. Cardiology · 2025Review
- Pyruvate kinase splice variants in fibroblasts influence cardiac remodeling after myocardial infarction in male mice.Journal of molecular and cellular cardiology · 2025Article
- Therapeutic targets for pulmonary arterial hypertension: insights into the emerging landscape.Expert opinion on therapeutic targets · 2025Review
- Integrating metabolomics and transcriptomics to analyze differences in muscle mass and flavor formation inFrontiers in veterinary science · 2025Article
- Glutamate enhances the production of inflammatory cytokines IL-6 and IL-11, as well as chemokines CXCL2, CXCL3, and CXCL8 in keloid fibroblasts.Frontiers in molecular biosciences · 2025Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundFibrosis and extracellular matrix remodeling are mediated by resident cardiac fibroblasts (CFs). In response to injury, fibroblasts activate, differentiating into specialized synthetic and contractile myofibroblasts producing copious extracellular matrix proteins (e.g., collagens). Myofibroblast persistence in chronic diseases, such as HF, leads to progressive cardiac dysfunction and maladaptive remodeling. We recently reported that an increase in αKG (alpha-ketoglutarate) bioavailability, which contributes to enhanced αKG-dependent lysine demethylase activity and chromatin remodeling, is required for myofibroblast formation. Therefore, we aimed to determine the substrates and metabolic pathways contributing to αKG biosynthesis and their requirement for myofibroblast formation.
methodsStable isotope metabolomics identified glutaminolysis as a key metabolic pathway required for αKG biosynthesis and myofibroblast formation, therefore we tested the effects of pharmacologic inhibition (CB-839) or genetic deletion of glutaminase (Gls1
resultsCarbon tracing indicated enhanced glutaminolysis mediating increased αKG abundance. Pharmacological and genetic inhibition of glutaminolysis prevented myofibroblast formation indicated by a reduction in αSMA+ cells, collagen gel contraction, collagen abundance, and the bioenergetic response. Inhibition of glutaminolysis also prevented TGFβ-mediated histone demethylation and supplementation with cell-permeable αKG rescued the myofibroblast phenotype. Importantly, inhibition of glutaminolysis was sufficient to prevent myofibroblast formation in CFs isolated from the human failing heart.
conclusionsThese results define glutaminolysis as necessary for myofibroblast formation and persistence, providing substantial rationale to evaluate several new therapeutic targets to treat cardiac fibrosis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.