Regulation of Endotoxin-Induced Proinflammatory Activation in Human Coronary Artery Cells: Expression of Functional Membrane-Bound CD14 by Human Coronary Artery Smooth Muscle Cells

Low-level endotoxemia has been identified as a powerful risk factor for atherosclerosis. However, little is known about the mechanisms that regulate endotoxin responsiveness in vascular cells. We conducted experiments to compare the relative responses of human coronary artery endothelial cells (HCAEC) and smooth muscle cells (HCASMC) to very low levels of endotoxin, and to elucidate the mechanisms that regulate endotoxin responsiveness in vascular cells. Endotoxin (</=1 ng/ml) caused production of chemotactic cytokines in HCAEC. Endotoxin-induced cytokine production was maximal at LPS-binding protein:soluble CD14 ratios <1, typically observed in individuals with subclinical infection; higher LPS-binding protein:soluble CD14 ratios were inhibitory. Endotoxin potently activated HCASMC, with cytokine release >10-fold higher in magnitude at >10-fold lower threshold concentrations (10-30 pg/ml) compared with HCAEC.…