Monocyte adherence to endothelium, a critical component of early atherogenesis implicated in the initiation of foam cell formation, is regulated by hemodynamic shear stress, inflammatory cytokines, and lysophosphatidylcholine (lyso-PC), the active component in oxidized low density lipoproteins. All three factors are also modulators of nitric oxide (NO) production. This project is designed to test the hypothesis that the regulation of monocyte adhesion to endothelium by hemodynamic shear stress, inflammatory cytokines, and lyso-PC in atherogenesis is at least in part regulated by the production and action of NO. Studies in specific aim 1 will determine the influence of NO on endothelial cell monocyte adhesion regulated by cytokines and lyso-PC, using inhibitors of NO to prevent its production free radical scavengers to prevent NO inactivation by cytokine-induced free radical generation and NO donors to determine causality for events regulated by NO.
Specific aim 2 using parallel plate flow chambers will determine the role of NO in shear stress modulation of endothelial cell adhesion to monocytes and the role of NO in shear-dependent regulation of endothelial cell response to different cytokines and lysoPC. Another key element in this proposal is the in vivo studies in specific aim 3. Using cholesterol-fed New Zealand White rabbits treated with NO synthase inhibitors these studies will examine the regulation by NO of monocyte adherence to vascular endothelium in artery rings at predilective atherosclerotic lesion sites at the intercostal artery flow dividers in the descending thoracic aorta by immunohistochemistry. Studies will determine the effects of cholesterol feeding and cytokine administration on monocyte adhesion. Also quantitative morphometric analysis of tissue segments will determine the role of NO in foam cell formation and accumulation at lesion-prone and lesion-resistant sites. Nitric oxide regulation of expression of endothelial cell adhesion proteins will be characterized by mRNA expression using northern blot analysis, surface immunofluorescent labelling, and blocking monoclonal antibodies in adhesion assays. The studies in this proposal will help to substantiate the role of NO in shear stress, cytokine, and lyso-PC regulation of monocyte adhesion both in vitro and in vivo and with help to elucidate the poorly understood cellular mechanism in early atherogenesis.
| Cayatte, A J; Rupin, A; Oliver-Krasinski, J et al. (2001) S17834, a new inhibitor of cell adhesion and atherosclerosis that targets nadph oxidase. Arterioscler Thromb Vasc Biol 21:1577-84 |
| Cayatte, A J; Du, Y; Oliver-Krasinski, J et al. (2000) The thromboxane receptor antagonist S18886 but not aspirin inhibits atherogenesis in apo E-deficient mice: evidence that eicosanoids other than thromboxane contribute to atherosclerosis. Arterioscler Thromb Vasc Biol 20:1724-8 |
