Genetic regulation of endothelial inflammatory responses in baboons.
OBJECTIVE
To investigate the genetic contributions to the expression of cell surface adhesion molecules on endothelial cells (ECs) and to the release by ECs of chemokines, which are responsible for local inflammation.


RESULTS
Monocyte adhesion to ECs and transmigration across the endothelial barrier are the key steps in the formation of atherosclerotic plaques and the rupture of the existing plaques. Biopsy specimens were obtained from the femoral arteries of 131 pedigreed baboons (65 males and 66 females) aged 10.4+/-1.5 years (mean+/-SD); arterial ECs were harvested and cultured up to the second passage and then subjected to in vitro challenge with tumor necrosis factor (TNF) alpha, 10 ng/mL, or vehicle for 4 hours. Endothelial surface adhesion molecules were measured using flow cytometry, and chemokines released by the ECs were measured by immunoassay. In response to TNF-alpha treatment, interleukin 8 and monocyte chemoattractant protein-1 released by ECs were increased 3.4- and 26-fold, respectively (P<0.001). The expressions of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 were increased 12.2-, 41.4-, and 3.5-fold, respectively (P<0.001). The quantitative levels of several traits were heritable after TNF-alpha stimulation: h(2)=0.24 (P=0.02) for interleukin 8 and h(2)=0.28 (P=0.003) for E-selectin in culture medium; h(2)=0.21 (P=0.03) for intercellular adhesion molecule-1; and h(2)=0.37 (P<0.001) for vascular cell adhesion molecule-1 expression on EC surfaces. Furthermore, significant heritability was observed for lysate protein level, which is a measure of cell growth rate, with (h(2)=0.64, P<0.001) or without (h(2)=0.51, P<0.001) TNF-alpha stimulation.


CONCLUSIONS
This study reports on the heritability of adhesion molecules in ECs when activated by TNF-alpha. This finding suggests genetic regulation of key arterial wall inflammatory processes that are responsible for the initiation of atherosclerotic lesions and the plaque rupture of existing atheromas.
Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, USA.
David L
DL
Rainwater
Qiang
Q
Shi
Michael C
MC
Mahaney
Vida
V
Hodara
John L
JL
Vandeberg
Xing Li
XL
Wang
D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D042783:Endothelial Cells / Q000276:immunology* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005838:Genotype; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000276:immunology; D010215:Papio; D010641:Phenotype; D019655:Quantitative Trait, Heritable; D012421:Rupture; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015815:Cell Adhesion Molecules; D018925:Chemokines; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha