Project description:We adopted a transcriptome-wide microarray analysis approach to determine the extent to which vascular gene expression is altered as a result of juvenile obesity and identify obesity-responsive mRNAs. We examined transcriptional profiles in the left anterior descending coronary artery (LAD), perivascular fat adjacent to the LAD, and descending thoracic aorta between obese (n=5) and lean (n=6) juvenile Ossabaw pigs (age=22 weeks). Obesity was experimentally induced by feeding the animals a high-fat/high fructose corn syrup/high-cholesterol diet for 16 weeks. We found that expression of 189 vascular cell genes in the LAD and expression of 165 genes in the thoracic aorta were altered with juvenile obesity (FDRM-bM-^IM-$10%) with an overlap of only 28 genes between both arteries. Notably, a number of genes found to be markedly up-regulated in the LAD of obese pigs are implicated in atherosclerosis, including ACP5, LYZ, CXCL14, APOE, PLA2G7, LGALS3, SPP1, ITGB2, CYBB, and P2RY12. Furthermore, pathway analysis revealed the induction of pro-inflammatory and pro-oxidant pathways with obesity primarily in the LAD. Gene expression in the LAD perivascular fat was minimally altered with juvenile obesity. Together, we provide new evidence that obesity produces artery-specific changes in pre-translational regulation with a clear up-regulation of pro-atherogenic genes in the LAD. Our data may offer potential viable drug targets and mechanistic insights regarding the molecular precursors involved in the origins of over-nutrition and obesity-associated vascular disease. In particular, our results suggest that the oxLDL-LOX-1-NFM-NM-:B signaling axis may be involved in the early initiation of a juvenile obesity-induced pro-atherogenic coronary artery phenotype. We examined transcriptional profiles in the left anterior descending coronary artery (LAD), perivascular fat adjacent to the LAD, and descending thoracic aorta between obese (n=5) and lean (n=6) juvenile Ossabaw pigs (age= 22 weeks). All three tissue types were taken from each animal, and each was applied to one and only one array array except a single Thoracic aorta (Animal ID 63 because there were not enough arrays), so there were 32 total arrays (11 unique pigs).

Project description:Diet induced obesity in swine was associated with altered cardiovascular functional, miR transcriptome, and proteomic response to ischemia-reperfusion. Furthermore, the GLP-1 mimetic exendin-4 altered functional, miR and protein responses differently in obese versus lean swine, demonstrating the pervasive effect of obesity on modulating cardiac response to pathophysiologies and therapeutics. This study tested the hypothesis that obesity alters the left ventricular microRNA (miR) transcriptome, proteome and functional cardiac response to ischemia-reperfusion (I/R) injury and to glucagon like peptide-1 (GLP-1) receptor activation. Ossabaw swine were fed normal chow or obesogenic diet for 6 months followed by IV infusion of either saline (vehicle) or the GLP-1 mimetic exendin-4 (Ex-4). Left ventricular pressure volume relationships were assessed under baseline conditions, during a 30-minute occlusion of the circumflex artery and during a 2 hour reperfusion period. Cardiac biopsies were obtained from normally-perfused and ischemia-reperfusion territories, and analyzed using Affymetrix 3.0 miR microarray and protein mass spectrometry. I/R was found to depress global cardiac function in lean swine (systolic pressure, end-diastolic volume). In contrast, Ex-4 therapies did not affect blood pressure in obese animals, but significantly reduced end-diastolic volume following the reperfusion period. These divergent physiologic response to regional I/R in obese vs lean hearts were associated with significantly different protein and miRNA changes. Obesity was associated with altered abundance of proteins associated with calcium handling and contractility, and with changes in miRs relating to metabolism, hypertrophy, and cell death, including the miR-15 and miR-30 families, miR-199a, and miR-214. These effects were modified differently by EX-4 treatment in lean vs obese swine. These findings suggest specific miR and proteomic differences contribute to differences in functional cardiac responses to ischemia-reperfusion injury and pharmacologic activation of GLP-1 signaling in the setting of obesity, volume, stroke volume and ejection fraction) with partial amelioration seen in Ex-4 treated animals.

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