Abstract-Oxidation of low density lipoprotein (LDL) phospholipids containing arachidonic acid at the sn-2 position occurs when a critical concentration of "seeding molecules" derived from the lipoxygenase pathway is reached in LDL. When this critical concentration is reached, the nonenzymatic oxidation of LDL phospholipids produces a series of biologically active, oxidized phospholipids that mediate the cellular events seen in the developing fatty streak. Normal high density lipoprotein (HDL) contains at least 4 enzymes as well as apolipoproteins that can prevent the formation of the LDL-derived oxidized phospholipids or inactivate them after they are formed. In the sense that normal HDL can prevent the formation of or inactivate these inflammatory LDL-derived oxidized phospholipids, normal HDL is anti-inflammatory. HDL from mice that are genetically predisposed to diet-induced atherosclerosis became proinflammatory when the mice are fed an atherogenic diet, injected with LDL-derived oxidized phospholipids, or infected with influenza A virus. Mice that were genetically engineered to be hyperlipidemic on a chow diet and patients with coronary atherosclerosis, despite normal lipid levels, also had proinflammatory HDL. It is proposed that LDL-derived oxidized phospholipids and HDL may be part of a system of nonspecific innate immunity and that the detection of proinflammatory HDL may be a useful marker of susceptibility to atherosclerosis. (Arterioscler Thromb Vasc Biol. 2001;21:481-488.)Key Words: HDL Ⅲ LDL Ⅲ atherosclerosis Ⅲ oxidized phospholipids T he events involved in fatty streak formation resemble those elicited by mycobacteria. 1 Over the past decade, there has been increasing evidence that this inflammatory response may, in part, be elicited by the oxidation of phospholipids contained in LDL. 2,3 Several oxidized phospholipids that are able to induce the genes and proteins necessary for the cellular response seen in the fatty streak have been identified in mildly oxidized LDL and in lesions of animal models of atherosclerosis. 4 -9 Two of these oxidized phospholipids, 1-palmitoyl-2(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine (POVPC) and 1-palmitoyl-2-glutaroyl-snglycero-3-phosphorylcholine (PGPC), both induced monocytes to bind to endothelial cells. 10 However, PGPC but not POVPC also induced neutrophils to bind to endothelial cells. 10 Indeed, POVPC strongly inhibited lipopolysaccharide-mediated induction of neutrophil binding and expression of E-selectin protein and mRNA. 10 This inhibition by POVPC was mediated by a protein kinase A-dependent pathway that resulted in downregulation of nuclear factor-B-dependent transcription. 10 PGPC, on the other hand, induced both E-selectin and vascular cell adhesion molecule-1 (VCAM-1) expression on endothelial cells. 10 On the basis of studies in Xenopus laevis oocytes, Leitinger et al 10 concluded that POVPC and PGPC bound to different receptors. Furthermore, they demonstrated that at concentrations equal to those present in mildly oxidized LDL, POVPC prevente...

Abstract-The attraction, binding, and entry of monocytes into the vessel wall play an important role in atherogenesis. We have previously shown that minimally oxidized/modified LDL (MM-LDL), a pathogenically relevant lipoprotein, can activate human aortic endothelial cells (HAECs) to produce monocyte chemotactic activators. In the present study, we demonstrate that MM-LDL and oxidation products of 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (PAPC) activate endothelial cells to synthesize monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8). Several lines of evidence suggest that this activation is mediated by the lipid-dependent transcription factor peroxisome proliferatoractivated receptor ␣ (PPAR␣), the most abundant member of the PPAR family in HAECs.

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The effects of testosterone on early atherogenesis and the role of aromatase, an enzyme that converts testosterone to estrogens, were assessed in low density lipoprotein receptor-deficient male mice fed a Western diet. Castration of male mice increased the extent of fatty streak lesion formation in the aortic origin compared with testes-intact animals. Administration of anastrazole, a selective aromatase inhibitor, to testes-intact males increased lesion formation to the same extent as that observed with orchidectomized animals. Testosterone supplementation of orchidectomized animals reduced lesion formation when compared with orchidectomized animals receiving the placebo. This attenuating effect of testosterone was not observed when the animals were treated simultaneously with the aromatase inhibitor. The beneficial effects of testosterone on early atherogenesis were not explained by changes in lipid levels. Estradiol administration to orchidectomized males attenuated lesion formation to the same extent as testosterone administration. Aromatase was expressed in the aorta of these animals as assessed by reverse transcription-PCR and immunohistochemistry. These results indicate that testosterone attenuates early atherogenesis most likely by being converted to estrogens by the enzyme aromatase expressed in the vessel wall.atherosclerosis ͉ androgens ͉ anastrazole ͉ mice ͉ estrogen

Background-Oxidized LDL has been found within the subendothelial space, and it exhibits numerous atherogenic properties, including induction of inflammatory genes. We examined the possibility that variations in endothelial response to minimally modified LDL (MM-LDL) constitute one of the genetic components in atherosclerosis. Methods and Results-By a novel explant technique, endothelial cells (ECs) were isolated from the aorta of inbred mouse strains with different susceptibilities to diet-induced atherosclerosis. Responses to MM-LDL were evaluated by examining the expression of inflammatory genes involved in atherosclerosis, including monocyte chemotactic protein-1 (MCP-1) and macrophage-colony-stimulating factor (M-CSF), an oxidative stress gene, heme oxygenase-1 (HO-1), and other, noninflammatory, genes. ECs from the susceptible mouse strain C57BL/6J exhibited dramatic induction of MCP-1, M-CSF, and HO-1, whereas ECs from the resistant strain C3H/HeJ showed little or no induction. In contrast, ECs from the 2 strains responded similarly to lipopolysaccharide. Conclusions-These data provide strong evidence that genetic factors in atherosclerosis act at the level of the vessel wall.(Circulation. 2000;102:75-81.)

Abstract-We report a combined genetic and genomic analysis of atherosclerosis in a cross between the strains C3H/HeJ and C57BL/6J on a hyperlipidemic apolipoprotein E-null background. We incorporated sex and sex-by-genotype interactions into our model selection procedure to identify 10 quantitative trait loci for lesion size, revealing a level of complexity greater than previously thought. Of the known risk factors for atherosclerosis, plasma triglyceride levels and plasma glucose to insulin ratios were particularly strongly, but negatively, associated with lesion size. We performed expression array analysis for 23 574 transcripts of the livers and adipose tissues of all 334 F2 mice and identified more than 10 000 expression quantitative trait loci that either mapped to the gene encoding the transcript, implying cis regulation, or to a separate locus, implying trans-regulation. The gene expression data allowed us to identify candidate genes that mapped to the atherosclerosis quantitative trait loci and for which the expression was regulated in cis. Genes highly correlated with lesions were enriched in certain known pathways involved in lesion development, including cholesterol metabolism, mitochondrial oxidative phosphorylation, and inflammation.

Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) differ significantly in atherosclerosis susceptibility and plasma lipid levels on the apolipoprotein E-deficient (apoE ÿ/ÿ ) background when fed a Western diet. To determine genetic factors contributing to the variations in these phenotypes, we performed quantitative trait locus (QTL) analysis using an intercross between the two strains carrying the apoE ÿ/ÿ gene. Atherosclerotic lesions at the aortic root and plasma lipid levels of 234 female F 2 mice were analyzed after being fed a Western diet for 12 weeks. QTL analysis revealed one significant QTL, named Ath22 (42 cM, LOD 4.1), on chromosome 9 and a suggestive QTL near D11mit236 (20 cM, LOD 2.4) on chromosome 11 that influenced atherosclerotic lesion size. One significant QTL on distal chromosome 1, which accounted for major variations in plasma LDL/VLDL cholesterol and triglyceride levels, coincided with a QTL having strong effects on body weight. Plasma LDL/VLDL cholesterol or triglyceride levels of F 2 mice were significantly correlated with body weight, but they were not correlated with atherosclerotic lesion sizes. These data indicate that atherosclerosis susceptibility and plasma cholesterol levels are controlled by separate genetic factors in the B6 and C3H mouse model and that genetic linkages exist between body weight and lipoprotein metabolism.

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