Background: MicroRNAs (miRNA) are single-stranded RNAs containing 18-24 nucleotides in length and have emerged as a prominent class of gene regulators. Due to their capacity to silence multiple target mRNAs and their reversible regulation, miRNA regulatory activity has been demonstrated in ischemia reperfusion (I/R) injury induced in non-heart transplantation settings. We propose that miRNA may be involved in I/R injury in heart transplantation by regulating downstream gene expression.
Methods: Hearts were excised from C57/BL6 mice, and perfused and preserved in UW solution at 4 0C for 18h to induce cold ischemia. After preservation hearts were implanted into syngeneic C57/BL6 recipients. Heart grafts were harvested for examination of the miRNA and gene expression by microarray assay. miRNA and gene expression were further confirmed by real time PCR. Histopathological change and apoptosis in heart grafts were examined by H&E staining and TUNEL.
Results: 18h cold ischemia caused graft dysfunction, histopathology changes and increased cell apoptotic cells in grafts. Using miRNA microarrays, we detected miRNA changes in the graft with prolonged cold ischemia (18h) on day 3 post transplantation. We found a total 14 miRNAs have been up-regulated by prolonged cold I/R as compared to grafts without cold ischemia, among which miR-711 was significantly increased up to 9 fold. In parallel, we analyzed for altered gene expression in heart grafts using gene expression microarrays. We found that 13 genes were up-regulated and 37 genes including a candidate downstream gene Angiopoietin 1 were down-regulated (>3 fold change, p<0.05). Hypoxia upregulated miR-711 expression while reduced the expression of Agiopoietin 1 in cardiomyocytes in vitro. Work is in progress to assess the effect of altering miR-711 expression on candidate genes.
Conclusion: This is the first demonstration that prolonged cold ischemia reperfusion changes miRNA expression profiles and gene expression profiles in syngeneic cardiac transplants. Further work is needed to test if miRNA is similarly involved in IRI using allogeneic heart transplants and whether miR-711 is directly affected by therapeutic strategies that alter I/R injury.
To cite this abstract in AMA style:Zhou L, Johnston N, Zhang X, Cheng D, Sui L, Luke P, Jevnikar A, Min W, Zheng X. Regulation of microRNA in Ischemia Reperfusion Injury in Heart Transplantation, The [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/regulation-of-microrna-in-ischemia-reperfusion-injury-in-heart-transplantation-the/. Accessed October 22, 2020.
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