Academic Journal
Cellular Retinoic Acid-Binding Protein 2 Promotes Ischemia-Induced Cardiac Fibroblast Activation and Fibrosis Through Suppression of MRE11-RAD50-NBS1-Mediated DNA Repair.
| Title: | Cellular Retinoic Acid-Binding Protein 2 Promotes Ischemia-Induced Cardiac Fibroblast Activation and Fibrosis Through Suppression of MRE11-RAD50-NBS1-Mediated DNA Repair. |
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| Authors: | Su Z; Department of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing China., Shen H; Department of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing China., Sun J; Department of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing China., Kong X; Department of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing China., Sun W; Department of Cardiology The First Affiliated Hospital with Nanjing Medical University Nanjing China. |
| Source: | Journal of the American Heart Association [J Am Heart Assoc] 2026 Aug 04; Vol. 15 (15), pp. e049049. Date of Electronic Publication: 2026 Jul 31. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101580524 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2047-9980 (Electronic) Linking ISSN: 20479980 NLM ISO Abbreviation: J Am Heart Assoc Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Oxford : Wiley-Blackwell |
| MeSH Terms: | MRE11 Homologue Protein*/metabolism , MRE11 Homologue Protein*/genetics , Myocardial Ischemia*/pathology , Myocardial Ischemia*/genetics , Myocardial Ischemia*/metabolism , Receptors, Retinoic Acid*/genetics , Receptors, Retinoic Acid*/metabolism , Cell Cycle Proteins*/metabolism , Cell Cycle Proteins*/genetics , Nuclear Proteins*/metabolism , Nuclear Proteins*/genetics , Fibroblasts*/metabolism , Fibroblasts*/pathology , DNA-Binding Proteins*/metabolism , DNA-Binding Proteins*/genetics , Myocardium*/pathology , Myocardium*/metabolism , DNA Repair Enzymes*/metabolism , DNA Repair Enzymes*/genetics , DNA Repair*, Acid Anhydride Hydrolases/metabolism ; Acid Anhydride Hydrolases/genetics ; Animals ; Humans ; Fibrosis ; Mice ; Disease Models, Animal ; Male ; Mice, Inbred C57BL ; Cells, Cultured ; Signal Transduction |
| Abstract: | Background: Cardiac fibrosis is a hallmark of ischemic heart failure and is driven by activated myofibroblasts. DNA damage and defective repair promote fibroblast activation, yet the upstream regulators that couple DNA damage responses to profibrotic remodeling remain unclear. Methods: Single-cell RNA sequencing data sets from human ischemic cardiomyopathy were analyzed to identify fibroblast-enriched candidate genes. In vivo, Postn promoter-driven adeno-associated viruses were used to knock down or overexpress CRABP2 (cellular retinoic acid-binding protein 2) in an isoproterenol-induced mouse model, followed by assessment of ventricular function and fibrosis. In vitro, neonatal cardiac fibroblasts were subjected to CRABP2 gain or loss of function and TGF-β (transforming growth factor-β) stimulation. Mechanistic studies combined RNA sequencing, immunoprecipitation-mass spectrometry, structural modeling, γ-H2AX staining, comet assays, and MRE11/MRE11-RAD50-NBS1 (MRN) perturbation. Results: Single-cell analyses identify CRABP2 as a fibroblast-enriched gene upregulated in profibrotic fibroblast subsets in human ischemic hearts. In vivo, CRABP2 knockdown in Postn+ myofibroblasts preserves left ventricular function and attenuates interstitial fibrosis, whereas CRABP2 overexpression exacerbates dysfunction and fibrosis in isoproterenol-treated mice. In vitro, CRABP2 promotes TGF-β-induced fibroblast migration, proliferation, activation, and collagen production. Mechanistically, CRABP2 binds MRE11, suppresses MRN-ATM-CHK2 signaling, and enhances DNA damage accumulation. Inhibiting or silencing MRE11 abrogates the antifibrotic and cardioprotective effects of CRABP2. Conclusions: CRABP2 drives profibrotic cardiac fibroblast activation by inhibiting MRE11/MRN-mediated DNA repair. The CRABP2-MRE11-MRN axis represents a potential therapeutic target for limiting fibrotic remodeling in ischemic heart failure. |
| Contributed Indexing: | Keywords: CRABP2; DNA repair; MRE11/MRN complex; cardiac fibroblasts; ischemic heart failure |
| Substance Nomenclature: | EC 3.1.- (MRE11 Homologue Protein) 0 (Receptors, Retinoic Acid) 0 (Cell Cycle Proteins) 0 (Nuclear Proteins) 0 (DNA-Binding Proteins) 0 (NBN protein, human) 0 (MRE11 protein, human) EC 3.6.- (Acid Anhydride Hydrolases) EC 3.6.- (RAD50 protein, human) EC 6.5.1.- (DNA Repair Enzymes) 0 (Nijmegen breakage syndrome 1 protein, mouse) 0 (Mre11a protein, mouse) |
| Entry Date(s): | Date Created: 20260731 Date Completed: 20260805 Latest Revision: 20260821 |
| Update Code: | 20260822 |
| DOI: | 10.1161/JAHA.126.049049 |
| PMID: | 42535577 |
| Database: | MEDLINE |
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