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Ischemic preconditioning affects long-term cell fate through DNA damage-related molecular signaling and altered proliferation

Kapoor, Sorabh
Bandi, Sriram
Gupta, Sanjeev
Published in American Journal of Pathology. 2014, vol. 184, no. 10, p. 2779-2790
Abstract Despite the potential of ischemic preconditioning for organ protection, long-term effects in terms of molecular processes and cell fates are ill defined. We determined consequences of hepatic ischemic preconditioning in rats, including cell transplantation assays. Ischemic preconditioning induced persistent alterations; for example, after 5 days liver histology was normal, but γ-glutamyl transpeptidase expression was observed, with altered antioxidant enzyme content, lipid peroxidation, and oxidative DNA adducts. Nonetheless, ischemic preconditioning partially protected from toxic liver injury. Similarly, primary hepatocytes from donor livers preconditioned with ischemia exhibited undesirably altered antioxidant enzyme content and lipid peroxidation, but better withstood insults. However, donor hepatocytes from livers preconditioned with ischemia did not engraft better than hepatocytes from control livers. Moreover, proliferation of hepatocytes from donor livers preconditioned with ischemia decreased under liver repopulation conditions. Hepatocytes from donor livers preconditioned with ischemia showed oxidative DNA damage with expression of genes involved in MAPK signaling that impose G1/S and G2/M checkpoint restrictions, including p38 MAPK-regulated or ERK-1/2-regulated cell-cycle genes such as FOS, MAPK8, MYC, various cyclins, CDKN2A, CDKN2B, TP53, and RB1. Thus, although ischemic preconditioning allowed hepatocytes to better withstand secondary insults, accompanying DNA damage and molecular events simultaneously impaired their proliferation capacity over the long term. Mitigation of ischemic preconditioning-induced DNA damage and deleterious molecular perturbations holds promise for advancing clinical applications.
Keywords AnimalsCarbon Tetrachloride/toxicityCell ProliferationDNA DamageDipeptidyl Peptidase 4/deficiency/geneticsDisease Models, AnimalHepatocytes/metabolismHumansIschemia/pathologyIschemic PreconditioningLipid PeroxidationLiver/blood supply/injuries/metabolismOxidative StressRatsReperfusion Injury/prevention & controlSignal Transductiongamma-Glutamyltransferase/genetics/metabolism
PMID: 25128377
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Research group Création de tissus par bio-ingénieurie et régénération d'organes (1021)
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KAPOOR, Sorabh et al. Ischemic preconditioning affects long-term cell fate through DNA damage-related molecular signaling and altered proliferation. In: The American Journal of Pathology, 2014, vol. 184, n° 10, p. 2779-2790. doi: 10.1016/j.ajpath.2014.07.002

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Deposited on : 2020-07-14

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