Circulating Oxidized Low-Density Lipoprotein and Its Association With Carotid Intima-Media Thickness in Asymptomatic Members of Familial Combined Hyperlipidemia Families

Abstract

Objective-Oxidized low-density lipoprotein (Ox-LDL)is implicated in the pathogenesis of atherosclerosis. Circulating oxidation-specific epitopes on plasma Ox-LDL has been linked with coronary artery disease, but its determinants and its association with early development of atherosclerosis in familial combined hyperlipidemia (FCHL) has not been very well studied. This study aimed to investigate the determinants of the circulating Ox-LDL and the association between Ox-LDL and carotid intima-media thickness (IMT) in asymptomatic members of FCHL families. Methods and Results-Ox-LDL, susceptibility of LDL to oxidation in vitro, plasma 8-isoprostane and antioxidants, lipids and lipoproteins, LDL particle size, and carotid IMT were measured in 150 asymptomatic FCHL family members. Affected FCHL family members had reduced LDL particle size and lag time for LDL oxidation, increased plasma levels of Ox-LDL, increased plasma urate and ␣-tocopherol, and a trend for the increase of 8-isoprostane as compared with nonaffected FCHL. Ox-LDL was independently associated with serum LDL cholesterol, apoB, and 8-isoprostane in multivariate analysis but only univariately correlated with LDL particle size and lag time for LDL oxidation. In addition, Ox-LDL was significantly associated with carotid mean IMT independently of other clinical and biochemical variables in a multivariate model. Conclusion-Serum LDL cholesterol, apoB levels, and 8-isoprostane were the most important determinants of Ox-LDL.Ox-LDL is independently associated with carotid IMT in asymptomatic FCHL family members and can be used as a marker of early atherosclerosis in FCHL. Key Words: carotid arteries Ⅲ hyperlipoproteinemia Ⅲ familial combined Ⅲ lipoproteins Ⅲ low-denisty lipoprotein Ⅲ oxygen radical Ⅲ ultrasonography T here is substantial evidence that oxidized low-density lipoprotein (Ox-LDL) is present in vivo within atherosclerotic lesions of arteries. 1 Under the oxidative stress, oxidative modification of LDL may take place in the subendothelial space of the arterial wall, 1 and a small amount of Ox-LDL may also be released into the circulation. 2 When "fully oxidized LDL" enters the circulation in minor quantities, it will be rapidly cleared by the reticuloendothelial system, particularly in the liver, or it will be removed by the preexisting circulating autoantibodies to In contrast, the "minimally modified LDL," in which oxidative modification has not been sufficient to cause changes recognized by scavenger receptors, can be found in circulation. 4,5 Other studies have defined the presence of oxidationspecific epitopes on plasma LDL 6 -8 or baseline levels of conjugated dienes in lipids extracted from LDL (LDL-BDC) as measures of LDL oxidation in vivo. 9 Recently, several groups have developed several specific methods to measure circulating Ox-LDL using different anti-Ox-LDL antibodies. 6 -8 As a sensitive biochemical marker, Ox-LDL has been related to coronary artery disease (CAD) in several clinical studies. 6,10 -12 Plasma Ox-LDL has also been associ...

Modulation of endothelial cell thrombomodulin by PPAR ligands — Variation according to environment

“…In particular when HAECs were incubated with fenofibrate in the presence of oxidized LDL the effect of the medication was reversed (Figure 1 and Figure 4). While it is impossible to replicate the atheromatous environment in vitro, both TNF-α and oxidized LDL have been demonstrated within atherosclerosis and shown to modulate TM expression, supporting the relevance of these studies [31][32][33][34][35]. There are a number of other mechanisms which may account for the inter-sample variation in response to PPAR ligand incubation in this study.…”

Carotid Intima-Media Thickness for Atherosclerosis

“…Although LDL is related to atherosclerosis, the oxidation of LDL was recently hypothesized to be important in the early development of atherosclerosis. Several studies have found that the oxidized LDL concentrations are associated with increased carotid IMT in the general population 75,76) , in familial hyperlipidemia families 77) , and in patients with coronary artery disease 78) . The serum level of LOX-1 ligand containing ApoB (LAB), which is considered a novel biomarker for predicting cardiovascular events, was found to be associated with carotid IMT in US Caucasian men but not Japanese men 79) .…”

Hereditary Deficiency of gp91 phox Is Associated With Enhanced Arterial Dilatation

“…phox , could play a role because its increase may directly affect NO 38 and isoprostanes 39 ; however, the relationship between ox-LDL and FMD is still unclear. 40 -42 Finally, we must take into account the possibility that some antibiotics may favorably affect FMD either directly, as in the case of azithromycin, 43 or indirectly through reduced serum cholesterol levels.…”