Differential gene responses three days following infarction in the fetal and adolescent sheep heart

Background: There are critical molecular mechanisms that can be activated to induce myocardial repair and in humans this is most efficient during fetal development. The timing of heart development in relation to birth and the size/electrophysiology of the heart are similar in humans and sheep, providing a model to investigate the repair capacity of the mammalian heart and how this can be applied to adult heart repair. Methods: Myocardial infarction was induced by ligation of the left anterior descending coronary artery in fetal (105d gestation when cardiomyocytes are proliferative) and adolescent sheep (6 months of age when all cardiomyocytes have switched to an adult phenotype). An ovine gene microarray was used to compare gene expression in sham and infarcted (remote, border and infarct areas) cardiac tissue from fetal and adolescent hearts. Results: The gene response to myocardial infarction was less pronounced in fetal compared to adolescent sheep hearts and there were unique gene responses at each age. There were also region-specific changes in gene expression between each age, in the infarct tissue, tissue bordering the infarct, and tissue remote from the infarction. In total, there were 880 genes that responded to MI uniquely in the adolescent samples compared with 170 genes in the fetal response, as well as 742 overlap genes that showed concordant direction of change responses to infarction at both ages. Conclusions: In response to myocardial infarction, there were specific changes in genes within pathways of mitochondrial oxidation, muscle contraction, and haematopoietic cell lineages, suggesting that the control of energy utilisation and immune function are critical for effective heart repair. The more restricted gene response in the fetus may be an important factor in its enhanced capacity for cardiac repair. 105 day gestation sheep fetuses and 6 month old adolescent sheep underwent surgery to ligate the second diagonal of the left anterior descending coronary artery causing myocardial infarction. Animals were then humanely killed three days after surgery and tissue from the infarct area, border zone and remote zone was collected for RNA extraction. Control animals recieved Sham surgery. Three samples from each tissue region (Sham, remote, border and infract) from both age groups (Fetal and Adolescent sheep) were used in total for array analysis. RNA was labelled with Cy3 and hybridized to Agilent 8 × 15k microarray slides (Ovine 019221 Arrays; GPL14112 platform) and scanned on an Agilent G2505B 2 dye scanner.