Changes in gene expression following cardiac pacing-induced delayed cardioprotection in the canine heart

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Understandingthe mechanism behind the cardioprotection induced by preconditioning might provide a new therapeutic tool against the life threateningventricular arrhythmias that often lead to sudden cardiac death. Thereforein Study I, we aimedto investigategene expression changes following ischemia and reperfusion in dogs subjected to rapid right ventricular cardiac pacing 24hours previously by a genome-wide approach using cDNA microarray analysis. We also aimed to examine the transcription rate of 45additional genes which havealready been suggestedto be involved inischemic PC but little is known about their role in the cardiac pacing induced antiarrhythmic protection. Furthermore, in Study II, 29genes were selected to explore the time course changes of gene expressions over 24 hours, which elapsesbetween rapid cardiac pacing and the ischemia/reperfusion period.In StudyI, we have identified 23 genes with altered expression; some of these, for example,MEF2A (involved in angiogenesis) or mAKAP (an anchoring protein), werefirstly demonstrated to be significantly up-regulated in response to preconditioning. We have proved that rapid right ventricular pacing alters theexpression of genes involved in the delayed protection. In Study I, 6out of 45 genes exhibited significant down-regulation and 16 showed up-regulationsin response to ischemia and reperfusion,compared withthe controldogs. Among these, genes encoding different proteins,such as NO producing enzymes, heat shock proteins, members of the survival signaling pathways or pro-apoptotic factors showed the most marked changes.In Study II, we have proved thatpacing inducestime-dependent alterationsin the expressionof the 29 genes examined.Immediately after the cessation of pacing, 8genesshowed significant up-regulation and 6 significantdown-regulation. After these initial changes, some of these early up-or down-regulated geneseitherremained unchangedorshowed a biphasic transcriptional pattern; i.e. after aninitial change in their transcriptionthese genes were normalizedto the mRNA level of the unpaced hearts but their expression started to changeagain at later time points. There were also genes, such as those encode eNOS and iNOS,which exhibited significant up-regulation only 12h after the pacing stimulus. The resultantincreaseineNOS protein content and activationcertainly contributes toan increased NO production, to which we attribute an important role in late phase of the protection.We are aware that changes atgene expression level do not always reflect changes atprotein level, neverthelessthepresent results provide evidence for gene expression changes following cardiac pacing,and when theantiarrhythmic protection is observed.

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