Effect of Oxysterol-Enriched Low-Density Lipoprotein on Endothelial Barrier Function in Culture

Abstract

High levels of plasma low-density lipoproteins (LDL) are known to be a risk factor for developing coronary artery disease although the specific mechanism involved is unknown. It may be related to effects of oxidized lipid components of LDL on vascular endothelial barrier function (EBF). This study addressed the hypothesis that LDL-associated products of cholesterol oxidation, oxysterols, decrease EBF resulting in increased penetration of blood components such as LDL into the arterial wall. LDL from human volunteers and rabbits was enriched with cholesterol or cholestan-3β, 5α, 6βtriol (Triol) by in vitro incubation. Exposure of cultured vascular endothelial cell monolayers to LDL enriched with Triol reduced EBF, measured as an increase in transendothelial albumin transfer, whereas cholesterol enrichment, like un-enriched LDL, had no effect on EBF. In a second experimental series, rabbits were gavaged with 100 mg of cholesterol or Triol/kg body weight, and LDL was isolated from serum 24 h after gavage. As was seen with the in vitro experiments, Triol-enriched LDL markedly decreased EBF. Similarly, LDL from cholesterol-gavaged rabbits reduced EBF, while LDL from vehicle treated rabbits had no effect. These results suggest that LDL-associated oxysterols are detrimental to normal barrier function of the vascular endothelium. Disruption of this barrier function may serve as an initiating factor in atherosclerotic lesion formation.

Pro‐oxidant effects of 7‐hydroperoxycholest‐5‐en‐3β‐ol on the copper‐initiated oxidation of low density lipoprotein

“…In vivo OS may partly be formed by reduction of cholesterol peroxides, as has been observed for hydroxy fatty acids. OS were first demonstrated to induce atherosclerosis in animals and to be toxic for vascular cells [16][17][18][19]. Epidemiological studies were conducted in Indian migrants in England who have a high incidence of atherosclerosis [19].…”

Cholesterol Oxidation Products Induce Vascular Foam Cell Lesion Formation in Hypercholesterolemic New Zealand White Rabbits

“…ChOx can induce endothelial dysfunction 12 or endothelial injury. 4 Previous studies have shown that certain ChOx and ChOxenriched LDL decreased vascular endothelial barrier functions, leading to increased transendothelial macromolecule transfer, 9,10,62,63 and that some ChOx strongly inhibit gap junction formation in fibroblasts. 64 Alternatively, apoptosis induced by ChOx leads to increased endothelial cell turnover, which is associated with increased endothelial transcytosis or permeability.…”

“…1 Studies specifically addressing this issue have shown that ChOx possess several characteristics that may promote atherosclerosis. These include cytotoxic/apoptotic potential to vascular cells such as fibroblasts, 2 endothelial cells, [3][4][5] and smooth muscle cells 6 -8 ; impairment of vascular endothelial barrier function 9,10 ; inhibition of endothelial NO release 11 and arterial relaxation 12 ; inhibition of cholesterol synthesis or utilization 13,14 ; perturbation of intracellular cholesterol trafficking [15][16][17] ; and activation of acyl CoA:cholesterol acyltransferase (ACAT) activity. 18,19 ChOx are abundant in oxidatively modified LDL (ox-LDL), 20 and high levels of circulating ChOx are found in rabbits fed a cholesterolcontaining diet.…”

Arterial Injury by Cholesterol Oxidation Products Causes Endothelial Dysfunction and Arterial Wall Cholesterol Accumulation

“…9 In addition, certain ChOx and ChOx-enriched LDL decrease vascular endothelial barrier function. 10,11 ChOx administered to animals by intravenous injection, oral feeding, and gavage have been reported to cause vascular injury. [12][13][14][15][16][17] However, the pharmacokinetics of ChOx are not well understood, nor are their vascular effects in the absence of hypercholesterolemia.…”