Prelesional arterial endothelial phenotypes in hypercholesterolemia: universal ABCA1 upregulation contrasts with region-specific gene expression in vivo.
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.
Civelek
Mete
M
Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
Grant
Gregory R
GR
Irolla
Chrysta R
CR
Shi
Congzhu
C
Riley
Rebecca J
RJ
Chiesa
Oscar A
OA
Stoeckert
Christian J
CJ
Karanian
John W
JW
Pritchard
William F
WF
Davies
Peter F
PF
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001158:Arteries / Q000473:pathology*; D050197:Atherosclerosis / Q000473:pathology*; D002469:Cell Separation; D002791:Cholesterol, Dietary / Q000633:toxicity; D004730:Endothelium, Vascular / Q000473:pathology*; D015870:Gene Expression / Q000502:physiology; D006937:Hypercholesterolemia / Q000473:pathology*; D006949:Hyperlipidemias / Q000473:pathology; D007150:Immunohistochemistry; D000071518:Liver X Receptors; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010641:Phenotype; D013552:Swine; D015854:Up-Regulation / Q000502:physiology
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002791:Cholesterol, Dietary; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors