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

Abstract

Abstract-Circulating cholesterol oxidation products (ChOx) have long been implicated in the etiology of early atherosclerosis; however, direct in vivo evidence elucidating their role in atherogenesis is only recently becoming available. This study investigated ChOx effects on vascular lesion formation in New Zealand White rabbits under controlled hypercholesterolemic conditions. By closely monitoring plasma cholesterol levels and adjusting dietary cholesterol intake during a 78-day period, total plasma cholesterol exposures (cumulative plasma cholesterol levels over time) were controlled between 27 000 and 34 000 mg/dLϫday (final plasma cholesterol concentration, 467Ϯ77 mg/mL), representing a threshold range for sudanophilic lesion formation in the aorta. Twenty injections of a ChOx mixture (70 mg per injection) were made bearing an oxysterol composition similar to that found in circulating oxidatively modified low density lipoprotein. At sacrifice, the ChOx-injected rabbits (nϭ5) had (1) significantly higher plasma ChOx levels, (2) significantly increased cholesterol content in the aortas, mainly as esterified cholesterol, and (3) significantly greater sudanophilic lesion size and frequency in the aortas compared with vehicle-injected control rabbits (nϭ5). The aortic cholesterol content and extent of sudanophilic lesion area were correlated significantly with total plasma ChOx exposure (PϽ0.003 and PϽ0.0001, respectively) but not with total cholesterol exposure. The results indicate that for moderate experimental hypercholesterolemia, a situation more relevant to physiological hypercholesterolemia in humans, circulating ChOx may play an important role in inducing formation of early atherosclerotic lesions. Because ChOx are often present in cholesterol-containing diets, foam cell lesion formation induced by ChOx rather than cholesterol cannot be overlooked.

NAD(P)H Oxidase Nox-4 Mediates 7-Ketocholesterol-Induced Endoplasmic Reticulum Stress and Apoptosis in Human Aortic Smooth Muscle Cells

“…In the present study, we used a 7-Kchol concentration of 40 g/ml, which is ϳ25-fold higher than levels found in human plasma after a fat-rich meal. However, this concentration is compatible with the high levels of oxidized lipids accumulated in advanced human atherosclerotic plaque and is close to the levels found in the plasma of (19) and cholesterol-fed rabbits (41). The constitutively active Nox proteins, which produce low levels of ROS under basal conditions, can be upregulated in the vascular wall by proinflammatory factors, such as growth factors and cytokines (16,47).…”

Probucol Reduces Oxysterol Formation in Hypertensive Rabbits

“…48 We recently reported that injection of oxysterols 49 increased the amount of oxysterol deposition in the aortic wall and when combined with cholesterol feeding also increased the deposition of cholesterol and fatty streak formation. 50 Oxysterol content in the aortic arch and abdominal aorta increased; however, the amount of oxysterols and extent of cholesterol deposition was much lower in the abdominal aorta. These differences indicate that factors such as shear force or humoral responses may influence the extent of oxidative stress, promoting the formation of lipid peroxidation products in areas of predilection.…”

Choroidal Vessel Wall: Hypercholesterolaemia-Induced Dysfunction and Potential Role of Statins

“…In addition, the formation of foam cells as a consequence of phagocytes from the macrophage-oxidized LDL has also been detected, with the retention of cholesterol in the vascular wall and the activation of ACAT (acetyl-cholesterol-acyl-transferase) [5], this point being key to the role of macrophages in the progression or regression of the lesions [4].…”

“…Both participate in the adhesion and extravasation of the monocytes into the subendothelial space, where they are transformed into macrophages. These subendothelial macrophages participate in transforming the LDL into highly oxidized LDL (oxLDL), which after being taken up by the macrophages contributes to the formation of foam cells [5] such as those seen in the large cho-roidal vessels and in the suprachoroid of hypercholesterolaemic rabbits [6]. The saturation of the foam cells leads to their death and the release of toxic products such as esterified and oxidized cholesterol, a scenario that inflicts greater endothelial damage and encourages the progression of the atherosclerotic lesion.…”