Transcriptional changes during hepatic ischemia-reperfusion in the rat

Autoři: Valerie Zabala aff001;  Joan M. Boylan aff001;  Paul Thevenot aff003;  Anderson Frank aff003;  Dewahar Senthoor aff004;  Varun Iyengar aff004;  Hannah Kim aff002;  Ari Cohen aff003;  Philip A. Gruppuso aff001;  Jennifer A. Sanders aff001
Působiště autorů: Department of Pediatrics, Rhode Island Hospital and Brown University, Providence, RI, United States of America aff001;  Division of Biology and Medicine, Brown University, Providence, RI, United States of America aff002;  Institute of Translational Research, Ochsner Health Systems, New Orleans LA, United States of America aff003;  Warren Alpert Medical School, Providence, RI, United States of America aff004;  Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, United States of America aff005;  Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, United States of America aff006
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


There are few effective targeted strategies to reduce hepatic ischemia-reperfusion (IR) injury, a contributor to poor outcomes in liver transplantation recipients. It has been proposed that IR injury is driven by the generation of reactive oxygen species (ROS). However, recent studies implicate other mediators of the injury response, including mitochondrial metabolic dysfunction. We examined changes in global gene expression after transient hepatic ischemia and at several early reperfusion times to identify potential targets that could be used to protect against IR injury. Male Wistar rats were subjected to 30 minutes of 70% partial warm ischemia followed by 0, 0.5, 2, or 6 hours of reperfusion. RNA was extracted from the reperfused and non-ischemic lobes at each time point for microarray analysis. Identification of differentially expressed genes and pathway analysis were used to characterize IR-induced changes in the hepatic transcriptome. Changes in the reperfused lobes were specific to the various reperfusion times. We made the unexpected observation that many of these changes were also present in tissue from the paired non-ischemic lobes. However, the earliest reperfusion time, 30 minutes, showed a marked increase in the expression of a set of immediate-early genes (c-Fos, c-Jun, Atf3, Egr1) that was exclusive to the reperfused lobe. We interpreted these results as indicating that this early response represented a tissue autonomous response to reperfusion. In contrast, the changes that occurred in both the reperfused and non-ischemic lobes were interpreted as indicating a non-autonomous response resulting from hemodynamic changes and/or circulating factors. These tissue autonomous and non-autonomous responses may serve as targets to ameliorate IR injury.

Klíčová slova:

Gene expression – Gene regulation – Ischemia – Liver transplantation – Regulator genes – Reperfusion – Transcription factors – Transient ischemic attacks


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