Entry of monocytes into the vessel wall is an important event in atherogenesis. Previous studies from our laboratory suggest that oxidized arachidonic acid-containing phospholipids present in mildly oxidized low density lipoproteins (MM-LDL) can activate endothelial cells to bind monocytes. In this study, biologically active oxidized arachidonic acid-containing phospholipids were produced by autoxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) and analyzed by liquid chromatography and electrospray ionization mass spectrometry in conjuction with biochemical derivatization techniques. We have now determined the molecular structure of two of three molecules present in MM-LDL and Ox-PAPC that induce monocyte-endothelial interactions. These lipids were identified as 1-palmitoyl-2-(5-oxovaleryl)-sn-glycero-3-phosphocholine (m/z 594.3) and 1-palmitoyl-2-glutaryl-snglycero-3-phosphocholine (m/z 610.2). These two molecules were produced by unambiguous total synthesis and found to be identical by analytical techniques and bioactivity assays to those present in MM-LDL and Ox-PAPC. Evidence for the importance of all three oxidized phospholipids in vivo was suggested by their presence in fatty streak lesions from cholesterol-fed rabbits and by their immunoreactivity with natural antibodies present in ApoE null mice. Overall, these studies suggest that specific oxidized derivatives of arachidonic acidcontaining phospholipids may be important initiators of atherogenesis.

As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.).

It has been postulated that low density lipoprotein (LDL) becomes fully atherogenic only if it first undergoes oxidative modification. The oxidatively modified form, but not native LDL, is recognized by the acetyl-LDL or "scavenger" receptor and could, therefore, be taken up rapidly by tissue macrophages to generate the fatty-streak lesion of atherosclerosis. However, there is thus far very little direct evidence for oxidative modification in vivo. The studies reported here take advantage of the fact that probucol is an effective antioxidant transported in lipoproteins, including LDL, and blocks the oxidative modification of LDL in vitro. We now show that the rate of degradation of LDL in the macrophage-rich fatty-streak lesions of the LDL receptor-deficient

We asked If the arterial sites most prone to early lesions In cholesterol-fed rabbits have higher permeabilities to low density lipoprotein (LDL) In normollpidemlc rabbits or If these sites become more permeable shortly after the onset of cholesterol feeding. We also considered whether the focal Increases In the concentration of LDL within the arterial wall In lesion-susceptible sites before fatty streak formation can be explained by Increased arterial permeability to LDL or by other mechanisms such as decreased rates of LDL efflux or degradation.