Gene expression profiling of prolonged cold ischemia and reperfusion in murine heart transplants

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Abstract
Heart transplantation causes complex changes in the biological homeostasis of the graft. Current knowledge is restricted to a few genes and regulation of certain factors involved in ischemia-reperfusion (I/R) injury. Efficient strategies to prevent I/R injury, however, require a better understanding of its mechanisms. Using cDNA microarrays, we investigated gene expression profiles of murine cardiac isografts. For microarray hybridization experiments, chips with 8,734 individual target sequences were used. Messenger RNA was extracted from hearts subjected to warm ischemia and different time periods of reperfusion or to prolonged cold ischemia or warm ischemia and transplantation. Native hearts served as controls. A set of 68 sequences was regulated in all hearts. In addition, grafts without cold ischemia showed differential expression of 65 sequences, which were not found in hearts transplanted after cold storage, and which in turn had 38 sequences regulated and not detected in grafts without cold ischemia. Overall, approximately 50% of regulated transcripts are expressed sequence tags (ESTs) with unknown function. Annotated genes encoded immune modulators (20% of sequences), receptor proteins, structural proteins, and proteins involved in metabolism. Our data demonstrate expression profiles of hearts subjected to prolonged cold ischemia or transplantation in an isogeneic setting. We have defined functional complexes and detected a substantial amount of ESTs encoding novel proteins. These studies may provide a molecular basis for further functional experiments and may help identify potential targets for modulation of postischemic inflammation.