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

Sorabh Kapoor, Ekaterine Berishvili, Sriram Bandi, Sanjeev Gupta

Research output: Contribution to journalArticle

6 Scopus citations

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 g-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 MAPKeregulated or ERK-1/ 2eregulated 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 preconditioningeinduced DNA damage and deleterious molecular perturbations holds promise for advancing clinical applications.

Original languageEnglish (US)
Pages (from-to)2779-2790
Number of pages12
JournalAmerican Journal of Pathology
Volume184
Issue number10
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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