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Article

Cyclophilin D Regulates the Nuclear Translocation of AIF, Cardiac Endothelial Cell Necroptosis and Murine Cardiac Transplant Injury

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Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, B4-231, 339 Windermere Road, London, ON N6A 5A5, Canada
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Department of Pathology, Western University, 1151 Richmond Street, London, ON N6A 3K7, Canada
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Department of Rheumatology and Immunology, The First Hospital of Jilin University, 3808 Jiefang Road, Changchun 130021, China
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Multi-Organ Transplant Program, London Health Sciences Centre, London, ON N6A 5A5, Canada
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Division of Nephrology, Department of Medicine, Western University, London, ON N6A 3K7, Canada
*
Author to whom correspondence should be addressed.
Academic Editor: Anastasios Lymperopoulos
Int. J. Mol. Sci. 2021, 22(20), 11038; https://doi.org/10.3390/ijms222011038
Received: 30 August 2021 / Revised: 23 September 2021 / Accepted: 8 October 2021 / Published: 13 October 2021
(This article belongs to the Special Issue Cell and Molecular Interactions in Blood Vessels 2021)
Ischemia-reperfusion injury (IRI) is an inevitable consequence of organ transplant procedure and associated with acute and chronic organ rejection in transplantation. IRI leads to various forms of programmed cell death, which worsens tissue damage and accelerates transplant rejection. We recently demonstrated that necroptosis participates in murine cardiac microvascular endothelial cell (MVEC) death and murine cardiac transplant rejection. However, MVEC death under a more complex IRI model has not been studied. In this study, we found that simulating IRI conditions in vitro by hypoxia, reoxygenation and treatment with inflammatory cytokines induced necroptosis in MVECs. Interestingly, the apoptosis-inducing factor (AIF) translocated to the nucleus during MVEC necroptosis, which is regulated by the mitochondrial permeability molecule cyclophilin D (CypD). Furthermore, CypD deficiency in donor cardiac grafts inhibited AIF translocation and mitigated graft IRI and rejection (n = 7; p = 0.002). Our studies indicate that CypD and AIF play significant roles in MVEC necroptosis and cardiac transplant rejection following IRI. Targeting CypD and its downstream AIF may be a plausible approach to inhibit IRI-caused cardiac damage and improve transplant survival. View Full-Text
Keywords: hypoxia; ischemia; necroptosis; CypD; AIF; endothelial cell; cardiac; transplantation hypoxia; ischemia; necroptosis; CypD; AIF; endothelial cell; cardiac; transplantation
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MDPI and ACS Style

Qamar, A.; Zhao, J.; Xu, L.; McLeod, P.; Huang, X.; Jiang, J.; Liu, W.; Haig, A.; Zhang, Z.-X. Cyclophilin D Regulates the Nuclear Translocation of AIF, Cardiac Endothelial Cell Necroptosis and Murine Cardiac Transplant Injury. Int. J. Mol. Sci. 2021, 22, 11038. https://doi.org/10.3390/ijms222011038

AMA Style

Qamar A, Zhao J, Xu L, McLeod P, Huang X, Jiang J, Liu W, Haig A, Zhang Z-X. Cyclophilin D Regulates the Nuclear Translocation of AIF, Cardiac Endothelial Cell Necroptosis and Murine Cardiac Transplant Injury. International Journal of Molecular Sciences. 2021; 22(20):11038. https://doi.org/10.3390/ijms222011038

Chicago/Turabian Style

Qamar, Adnan, Jianqi Zhao, Laura Xu, Patrick McLeod, Xuyan Huang, Jifu Jiang, Weihua Liu, Aaron Haig, and Zhu-Xu Zhang. 2021. "Cyclophilin D Regulates the Nuclear Translocation of AIF, Cardiac Endothelial Cell Necroptosis and Murine Cardiac Transplant Injury" International Journal of Molecular Sciences 22, no. 20: 11038. https://doi.org/10.3390/ijms222011038

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