Prelesional arterial endothelial phenotypes in hypercholesterolemia: universal ABCA1 upregulation contrasts with region-specific gene expression in vivo

Abstract

Atherosclerosis originates as focal arterial lesions having a predictable distribution to regions of bifurcations, branches, and inner curvatures where blood flow characteristics are complex. Distinct endothelial phenotypes correlate with regional hemodynamics. We propose that systemic risk factors modify regional endothelial phenotype to influence focal susceptibility to atherosclerosis. Transcript profiles of freshly isolated endothelial cells from three atherosusceptible and three atheroprotected arterial regions in adult swine were analyzed to determine the initial prelesional effects of hypercholesterolemia on endothelial phenotypes in vivo. Cholesterol efflux transporter ATP-binding cassette transporter A1 (ABCA1) was upregulated at all sites in response to short-term high-fat diet. Proinflammatory and antioxidative endothelial gene expression profiles were induced in atherosusceptible and atheroprotected regions, respectively. However, markers for endoplasmic reticulum stress, a signature of susceptible endothelial phenotype, were not further enhanced by brief hypercholesterolemia. Both region-specific and ubiquitous (ABCA1) phenotype changes were identified as early prelesional responses of the endothelium to hypercholesterolemia. microarray; hypercholesterolemia; Oil Red O; endoplasmic reticulum stress; unfolded protein response

Gene Expression Analyses of Mouse Aortic Endothelium in Response to Atherogenic Stimuli

“…Among these genes are some that have been described previously as playing a role in the atherosclerotic endothelium, particularly Abca1 . This gene has been identified as upregulated in the swine endothelium in response to a brief hypercholesterolemic diet, 7 a finding that is consistent with its regulation in our ApoE −/− hyperlipidemic and acute hyperlipidemic mice. The protein encoded by Abca1 has been shown to modulate the transport of phospholipids and cholesterol to apo AI through the endothelial layer and is atheroprotective in vascular ECs because of this role in cholesterol efflux.…”

“…Similar studies on ECs isolated from swine maintained on a brief hypercholesterolemic diet supported these findings and reported an upregulation of ABCA1 in response to diet across all regions tested. 7 Although swine is a useful model of human atherosclerosis and its size allows for successful in vivo endothelial expression studies, there are significant limitations for their use in genetic studies. Although the small size of the mouse aorta does not allow for the spatial resolution achieved in swine, inbred mouse strains allow for genetic manipulation, biological replicates, and more high-throughput approaches.…”

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).…”

Sterol Regulatory Element Binding Protein 2 Activation of NLRP3 Inflammasome in Endothelium Mediates Hemodynamic-Induced Atherosclerosis Susceptibility

“…Conversely, the atheroprotective flow patterns should induce liver X receptors and hence up-regulate ABCA1 to facilitate reverse cholesterol transport 35 . Civelek et al reported no site-specific differences in endothelial ABCA1 expression between susceptible and protected sites of swine arteries 36 . However, our published work showed that ABCA1 level is lower in the mouse aortic arch compared with thoracic aorta 35 .…”