Mediators of rat ischemic hepatic preconditioning after cold preservation identified by microarray analysis

Abstract

Hepatic ischemia-reperfusion injury associated with liver transplantation is an as yet unresolved problem in clinical practice. Preconditioning protects the liver against the deleterious effects of ischemia, although the mechanism underlying this preconditioning is still unclear. To profile gene expression patterns involved in hepatic ischemic preconditioning, we analyzed the changes in gene expression in rat livers by DNA microarray analysis. Approximately 116 genes were found to have altered gene expression after 8 hours of cold ischemia. Moreover, the expression of 218 genes was modified by classic preconditioning followed by the same ischemia process. Given the importance of the effects of ischemic preconditioning (IP) in minimizing the liver damage induced by sustained ischemia before reperfusion, this study analyzed the putative genes involved in the beneficial role of IP in liver grafts undergoing cold ischemia before its implantation in the recipient (IPϩI). Great differences were found in the gene expression pattern of ischemic preconditioning ϩ long cold ischemia (IPϩI) group when compared with the long cold ischemia alone condition (I), which could explain the protective regulatory mechanisms that take place after preconditioning. Twenty-six genes that were downregulated in cold ischemia were found upregulated after preconditioning preceding a long cold ischemia period. These would be genes activated or maintained by preconditioning. Heat shock protein genes and 3-hydroxy-3-methylglutaryl-coenzyme A reductase are among the most markedly induced transcripts.

Over-expression of growth differentiation factor 15 (GDF15) preventing cold ischemia reperfusion (I/R) injury in heart transplantation through Foxo3a signaling

“…GDF15 expression has been linked to either anti- or pro-apoptotic function in several disease models. It is conceivable that GDF15 plays a pro-apoptotic protein role in cancer cells, whereas GDF15 acts as an anti-apoptotic protein in non-cancer cells [14, 33, 34]. The latter was described by Kempf and colleagues, who discovered GDF15 induction in the heart as a defense mechanism from warm I/R injury by reducing apoptosis in a coronary artery ligation model [13].…”

“…It is known to have pleiotropic functions involving stress response, inflammation, tumorigenesis, metastasis, angiogenesis, and tissue injury and recovery pathways [12]. It has been reported that GDF15 is upregulated in ischemic heart tissues in ae coronary artery ligation model [13], in rat liver tissues exposed to ischemic preconditioning before ischemia [14] and in the heart in response to hypertrophic conditions [15]. This quick up-regulation of GDF15 is aimed at preventing cells from further damage [13, 14].…”

“…It has been reported that GDF15 is upregulated in ischemic heart tissues in ae coronary artery ligation model [13], in rat liver tissues exposed to ischemic preconditioning before ischemia [14] and in the heart in response to hypertrophic conditions [15]. This quick up-regulation of GDF15 is aimed at preventing cells from further damage [13, 14]. A more recent study by Zhang [16], reported that the expression of GDF15 was up-regulated in myocardial tissues after undergoing I/R, and that this up-regulation of GDF15 reached a peak at 24h after reperfusion in a rat descending artery ligation myocardia I/R model with 1h ischemia.…”

Association of MicroRNA-223 Expression with Hepatic Ischemia/Reperfusion Injury in Mice

“…These results provided evidence that miR-223 may be somehow involved in the process of hepatic I/R injury. Hepatic I/R injury is a complex physiological process that is associated with the interaction of many genes and proteins [10][11][12]25]. MiRNAs are known to be important mediators of gene regulation in response to cell-to-cell signaling and act in negative feedback of gene regulation [26].…”

“…It is believed that these events are partially medicated by alteration in molecular processes such as transcription and translation [10][11][12]. MicroRNAs (miRNAs) are a class of endogenously expressed small non-coding RNAs that are involved in regulation of translation and degradation of messenger RNA (mRNA) [13].…”