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Oxidative modification of low density lipoprotein (LDL) has been implicated in atherogenesis. Evidence consistent with this hypothesis includes the presence of oxidized lipids in atherosclerotic lesions, the newly discovered biological properties conferred on LDL by oxidation and the acceleration of atherogenesis by in vivo delivery of the gene for 15-lipoxygenase, an oxidizing enzyme present in atherosclerotic lesions. However, it is still unknown whether oxidative stress actually coincides with the evolution of the disease or whether it is of functional relevance to atherogenesis in vivo. Isoprostanes are products of arachidonic acid catalyzed by free radicals, which reflect oxidative stress and lipid peroxidation in vivo. Elevation of tissue and urinary isoprostanes is characteristic of human atherosclerosis. Here, deficiency in apolipoprotein E in the mouse (apoE-/-) resulted in atherogenesis and an increase in iPF2alpha-VI, an F2-isoprostane, in urine, plasma and vascular tissue. Supplementation with vitamin E significantly reduced isoprostane generation, but had no effect on plasma cholesterol levels in apoE-/- mice. Aortic lesion areas and iPF2alpha-VI levels in the arterial wall were also reduced significantly by vitamin E. Our results indicate that oxidative stress is increased in the apoE-/- mouse, is of functional importance in the evolution of atherosclerosis and can be suppressed by oral administration of vitamin E.

Prostaglandin D 2 (PGD 2 ) is released following exposure of asthmatics to allergen and acts via the adenylyl cyclase-coupled receptor for PGD 2 (DP receptor). In this study, it is reported that human eosinophils possess this receptor, which would be expected to inhibit their activation. In contrast, it was found that prostaglandin D 2 is a potent stimulator of eosinophil chemotaxis, actin polymerization, CD11b expression, and Lselectin shedding. These responses are specific for eosinophils, as neutrophils display little or no response to prostaglandin D 2 . They were not due to interaction with receptors for other prostanoids, as prostaglandins E 2 and F 2␣ , U46619 (a thromboxane A 2 analogue), and carbaprostacyclin (a prostacyclin analogue) displayed little or no activity. Furthermore, they were not shared by the selective DP receptor agonist BW245C and were not prevented by the selective DP receptor antagonist BWA868C, indicating that they were not mediated by DP receptors. In contrast, the prostaglandin D 2 metabolite 13,14-dihydro-15-oxoprostaglandin D 2 induced eosinophil activation but did not stimulate DP receptor-mediated adenosine 3,5-cyclic monophosphate (cAMP) formation. These results indicate that in addition to the classic inhibitory DP 1 receptor, eosinophils possess a second, novel DP 2 receptor that is associated with PGD 2 -induced cell activation. These 2 receptors appear to interact to regulate eosinophil responses to PGD 2 , as blockade of DP 1 receptor-mediated cAMP production by BWA868C resulted in enhanced DP 2 receptor-mediated stimulation of CD11b expression. The balance between DP 1 and DP 2 receptors could determine the degree to which prostaglandin D 2 can activate eosinophils and may play a role in eosinophil recruitment in asthma. (Blood. 2001;98:1942-1948

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