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Single nuclei RNA-seq of Ossabaw pig atherosclerotic and healthy aortae

ABSTRACT: Atherosclerosis is a major contributor to cardiovascular diseases. Well-established preclinical models that can accurately recapitulate human atherosclerosis development and progression are necessary for developing new therapeutics. Pig models are extensively used in cardiovascular research due to their physiological similarities to humans. However, their translational efficacy into clinical settings has remained limited. To ensure better translational outcomes, a deeper molecular characterization of atherosclerotic disease mechanisms in swine models is urgently required. Methods: To address this gap, we employed single nuclei transcriptomics to characterize healthy and atherosclerotic aortas in the Ossabaw pig model. We analyzed over 36,000 nuclei from aortas of 5 adult male castrated pigs kept on atherogenic and chow diets. In-depth single-nuclei transcriptomic and cell-cell communication analyses were undertaken to uncover molecular changes in swine atherosclerosis development. Comparisons to human and mouse atherosclerosis were used to establish the veracity of the Ossabaw pig in modeling human disease.

ORGANISM(S): Sus scrofa

PROVIDER: GSE274218 | GEO | 2025/08/10

REPOSITORIES: GEO

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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).

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Single nuclei RNA-seq of Ossabaw pig atherosclerotic and healthy aortae

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