No abstract

Oxidized lipoproteins may be important in the pathogenesis of atherosclerosis. Because diabetic subjects are particularly prone to vascular disease, and glucose autoxidation and protein glycation generate reactive oxygen species, we explored the role of glucose in lipoprotein oxidation. Glucose enhanced low density lipoprotein (LDL) oxidation at concentrations seen in the diabetic state. Conjugated dienes, thiobarbituric acid reactive substances, electrophoretic mobility, and degradation by macrophages were increased when LDL was modified in the presence of glucose. In contrast, free lysine groups and fibroblast degradation were reduced. Although loss of reactive lysine groups could be due to either oxidative modification or nonenzymatic glycation of apolipoprotein B-100, inhibition of lipid peroxidation by the metal chelator, diethylenetriamine pentaacetic acid, blocked the changes in free lysines. Thus, glycation of lysine residues is unlikely to account for the alterations in macrophage and fibroblast uptake of LDL modified in the presence of glucose. Glucose-mediated enhancement of LDL oxidation was partially blocked by superoxide dismutase and nearly completely inhibited by butylated hydroxytoluene. These findings indicate that glucose enhances LDL lipid peroxidation by an oxidative pathway involving superoxide and raise the possibility that the chronic hyperglycemia of diabetes accelerates lipoprotein oxidation, thereby promoting diabetic vascular disease. (J. Clin. Invest. 1994. 94:771-778.)

No abstract

Objective-Plasma platelet-activating factor (PAF) acetylhydrolase (AH) is an enzyme bound with lipoproteins that degrades not only PAF but also PAF-like oxidized phospholipids that are proposed to promote atherosclerosis. In this study, we investigated the distribution of PAF-AH protein among lipoprotein classes by using adenovirus-mediated gene transfer in mice, and we examined its effects on lipoprotein oxidation and foam cell formation of macrophages. Methods and Results-Adenovirus-mediated overexpression of PAF-AH in mice resulted in a 76-to 140-fold increase in plasma PAF-AH activity. Contrary to the previous report, overexpressed human PAF-AH protein was bound to very low density lipoprotein, intermediate density lipoprotein, low density lipoprotein, and high density lipoprotein (HDL). All the lipoproteins with overexpressed human PAF-AH revealed more resistance against oxidative stress, which was associated with lower levels in autoantibody against oxidized low density lipoprotein in the plasma. In addition, HDL with human PAF-AH inhibited foam cell formation and facilitated cholesterol efflux in macrophages. Key Words: platelet-activating factor acetylhydrolase Ⅲ oxidative stress Ⅲ adenovirus Ⅲ foam cell formation Ⅲ cholesterol efflux P latelet-activating factor (PAF) acetylhydrolase (AH) is a calcium-independent enzyme that degrades PAF, a bioactive phospholipid mediator for allergic and inflammatory processes, to a biologically inactive lyso-PAF. Plasma PAF-AH, 1 of the 3 PAF-AH isoforms identified so far, is produced from macrophages and exists in the plasma in the form bound with lipoproteins; the other 2 isoforms are found only in tissues. Seventy percent to 83% of the plasma PAF-AH protein exists on LDL, and 11% to 30% exists on HDL in human plasma. 1,2 An interchange between the 2 lipoproteins has been reported in plasma PAF-AH. 1 In mice, it has been recognized that PAF-AH is associated primarily with HDL and minimally with VLDL 3,4 and that neither murine PAF-AH nor human PAF-AH has been proposed to bind to murine LDL. 5 An observational study has shown that plasma PAF-AH activity is altered in atherosclerotic diseases. 6 Oxidation of LDL, in which PAF-like oxidized phospholipids are produced on the LDL surface, is one of the key factors in the early stages of atherosclerosis. 7 Besides catalyzing PAF, plasma PAF-AH protein hydrolyzes PAF-like oxidized phospholipids, thereby most likely inactivating the biologically active mediator. However, the products of this reaction include oxidized fatty acids and lysophosphatidylcholine, 8 which are potentially inflammatory mediators that could amplify atherogenesis. Therefore, it is not fully clear whether PAF-AH is antiatherogenic or proatherogenic in humans. There was one report documenting that high PAF-AH activity is associated with an increased risk of coronary artery disease in humans. 6 However, it is not conclusive whether PAF-AH is a causative agent of coronary artery disease or just a marker. A recent animal study demonstrated that overexpressi...

No abstract