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Cirbp suppression compromises DHODH-mediated ferroptosis defense and attenuates hypothermic cardioprotection in an aged donor transplantation model
Yifan Zhu, … , Hao Zhang, Yiwei Liu
Yifan Zhu, … , Hao Zhang, Yiwei Liu
Published May 1, 2024
Citation Information: J Clin Invest. 2024;134(9):e175645. https://doi.org/10.1172/JCI175645.
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Cirbp suppression compromises DHODH-mediated ferroptosis defense and attenuates hypothermic cardioprotection in an aged donor transplantation model

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Abstract

Hypothermia is commonly used to protect donor hearts during transplantation. However, patients transplanted with aged donor hearts still have severe myocardial injury and decreased survival rates, but the underlying mechanism remains unknown. Because aged hearts are not considered suitable for donation, the number of patients awaiting heart transplants is increasing. In this study, we examined whether hypothermic cardioprotection was attenuated in aged donor hearts during transplantation and evaluated potential therapeutic targets. Using a rat heart transplantation model, we found that hypothermic cardioprotection was impaired in aged donor hearts but preserved in young donor hearts. RNA-Seq showed that cold-inducible RNA-binding protein (Cirbp) expression was decreased in aged donor hearts, and these hearts showed severe ferroptosis after transplantation. The young donor hearts from Cirbp-KO rats exhibited attenuated hypothermic cardioprotection, but Cirbp overexpression in aged donor hearts ameliorated hypothermic cardioprotection. Cardiac proteomes revealed that dihydroorotate dehydrogenase (DHODH) expression was significantly decreased in Cirbp-KO donor hearts during transplantation. Consequently, DHODH-mediated ubiquinone reduction was compromised, thereby exacerbating cardiac lipid peroxidation and triggering ferroptosis after transplantation. A cardioplegic solution supplemented with CIRBP agonists improved hypothermic cardioprotection in aged donor hearts, indicating that this method has the potential to broaden the indications for using aged donor hearts in transplantation.

Authors

Yifan Zhu, Chenyu Jiang, Jian He, Chen He, Xingliang Zhou, Xu Huang, Yi Shen, Liwei Wu, Yongnan Li, Bei Feng, Yi Yan, Jun Li, Hao Zhang, Yiwei Liu

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Figure 6

Ferroptosis is exacerbated in Cirbp-KO cardiomyocytes after cold ischemia.

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Ferroptosis is exacerbated in Cirbp-KO cardiomyocytes after cold ischemi...
(A) Experimental design of the first part. The cardiomyocytes were isolated from WT or Cirbp-KO neonatal rats and subjected to cold ischemia. Both groups were treated with UW solution during cold ischemia. (B) Cardiomyocytes labeled with BODIPY 581/591 C11 after cold ischemia. The graph shows the ratio of oxidized–to–total BODIPY 581/591 C11. Ox., oxidized; Non-ox., nonoxidized. Scale bars: 25 μm. (C) MDA levels in cardiomyocytes after cold ischemia. (D) 4-HNE staining of cardiomyocytes after cold ischemia. Scale bars: 25 μm. (E) Western blotting and quantification of CIRBP, ACSL4, and PTGS2 in cardiomyocytes after cold ischemia. (F) Cell viability of cardiomyocytes after cold ischemia. (G) Live-cell imaging of cardiomyocytes incubated with SYTOX Green after cold ischemia. Scale bars: 300 μm. (H) Time-lapse analysis of cell death in cardiomyocytes after cold ischemia. (I) Experimental design of the second part. The cardiomyocytes were isolated from Cirbp-KO neonatal rats and subjected to cold ischemia. One group is treated with UW solution and the other group is treated with UW solution supplemented with liproxstatin-1. (J) Cardiomyocytes labeled with BODIPY 581/591 C11 after cold ischemia. Scale bars: 25 μm. (K) Levels of MDA in cardiomyocytes after cold ischemia. (L) 4-HNE staining of cardiomyocytes after cold ischemia. Scale bars: 25 μm. (M) Western blotting and quantification of ACSL4 and PTGS2 in cardiomyocytes after cold ischemia. (N) Cell viability of cardiomyocytes after cold ischemia. (O) Live-cell imaging of cardiomyocytes incubated with SYTOX Green after cold ischemia. Scale bars: 300 μm. (P) Time-lapse analysis of cell death in cardiomyocytes after cold ischemia. SG, SYTOX green. Data shown are the mean ± standard deviation, with individual values presented as a dot plot. *P < 0.05, *P < 0.01, and ***P < 0.001, by Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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