Coronary Artery Endothelial Transcriptome In Vivo

Abstract

Background Endothelial function is central to the localization of atherosclerosis. The in vivo endothelial phenotypic footprints of arterial bed identity and site-specific athero-susceptibility are addressed. Methods and Results 98 endothelial cell samples from 13 discrete coronary and non-coronary arterial regions of varying susceptibilities to atherosclerosis were isolated from 76 normal swine. Transcript profiles were analyzed to determine the steady state in vivo endothelial phenotypes. An unsupervised systems biology approach utilizing weighted gene co-expression networks determined highly correlated endothelial genes. Connectivity network analysis identified 19 gene modules, 12 of which showed significant association with circulatory bed classification. Differential expression of 1,300 genes between coronary and non-coronary artery endothelium suggested distinct coronary endothelial phenotypes with highest significance expressed in gene modules enriched for biological functions related to endoplasmic reticulum (ER) stress and unfolded protein binding, regulation of transcription and translation, and redox homeostasis. Furthermore, within coronary arteries comparison of endothelial transcript profiles of susceptible proximal regions to protected distal regions suggested the presence of ER stress conditions in susceptible sites. Accumulation of reactive oxygen species (ROS) throughout coronary endothelium was greater than in non-coronary endothelium consistent with coronary artery ER stress and the lower endothelial expression of anti-oxidant genes in coronary arteries. Conclusions Gene connectivity analyses discriminated between coronary and non-coronary endothelial transcript profiles and identified differential transcript levels associated with increased ER and oxidative stress in coronary arteries, consistent with enhanced susceptibility to atherosclerosis.

Vascular transcriptional alterations produced by juvenile obesity in Ossabaw swine

“…We found that the LAD, a classically "atheroprone" coronary artery in adulthood (2,18), is more susceptible to transcriptional alterations as a result of juvenile obesity, compared with the more "atheroresistant" descending thoracic aorta (17). Notably, we identified a number of genes in the LAD (e.g., ACP5, LYZ, CXCL14, APOE, PLA2G7, LGALS3, SPP1, ITGB2, CYBB, P2RY12) that are implicated in atherosclerosis based on published literature (1, 10, 22-24, 27, 32, 33, 45, 48, 51, 56, 64, 74, 77, 84) and whose expression was markedly upregulated with juvenile obesity.…”

“…Because it is well established that coronary arteries, particularly the LAD, are highly susceptible to atherosclerosis (2,18) relative to other vascular beds such as the descending thoracic aorta (17), the changes in vascular gene expression produced by juvenile obesity that are exclusive to the LAD are of particular interest. In this regard, a number of genes found to be markedly upregulated in the LAD of obese pigs are implicated in the progression of atherosclerosis, including ACP5, LYZ, CXCL14, APOE, PLA2G7, LGALS3, SPP1, ITGB2, CYBB, and P2RY12 (Table 3) (1, 10, 22-24, 27, 32, 33, 45, 48, 51, 56, 64, 74, 77, 84).…”

“…Moreover, using state-of-the-art bioinformatic techniques we examined the impact of juvenile obesity on gene networks and interactions between individual components of these networks. In general, we hypothesized that juvenile obese pigs, relative to lean pigs, would exhibit altered expression of vascular cell genes involved in inflammation and oxidative stress pathways and that such between-group differences would be most pronounced in the LAD as this artery is highly susceptible to atherosclerosis in adulthood (2,18). Furthermore, in view of the evidence that altered expression and secretion of inflammatory cytokines from adipose tissue may contribute to the initiation and progression of atherosclerosis associated with obesity (13,65,66), we hypothesized that alterations in gene expression in the LAD induced by juvenile obesity would be accompanied by an increased expression of proinflammatory genes in the surrounding perivascular fat.…”

Heart failure: a complex clinical process interpreted by systems biology approach and network medicine

“…Thus, biological networks and modules have been described in atherosclerosis, like the transcriptomic modules derived from transcriptomic data of the Karolinska University Hospital, and constructed a gene association and correlation network of atherosclerosis (29). The coronary artery endothelial transcriptome was addressed in an experimental study and the transcript profiles were analyzed to identify the in vivo endothelial phenotypes (30). In a gene connectivity network analysis, specific coronary endothelial phenotypes expressed in gene modules were related to increased endoplasmic reticulum and oxidative stress in coronary arteries prone to atherosclerosis (30).…”

“…The coronary artery endothelial transcriptome was addressed in an experimental study and the transcript profiles were analyzed to identify the in vivo endothelial phenotypes (30). In a gene connectivity network analysis, specific coronary endothelial phenotypes expressed in gene modules were related to increased endoplasmic reticulum and oxidative stress in coronary arteries prone to atherosclerosis (30).…”