DOI: 10.1161/jaha.126.049049 ISSN: 2047-9980

Cellular Retinoic Acid–Binding Protein 2 Promotes Ischemia‐Induced Cardiac Fibroblast Activation and Fibrosis Through Suppression of MRE11‐RAD50‐NBS1–Mediated DNA Repair

Zhenyang Su, Hui Shen, Jinyu Sun, Xiangqing Kong, Wei Sun
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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.

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