Rapid Restoration of Normal Endothelial Functions in Genetically Hyperlipidemic Mice by a Synthetic Mediator of Reverse Lipid Transport

Abstract

Abstract-Endothelial dysfunction is a major pathophysiological consequence of hypercholesterolemia and other conditions. We examined whether a synthetic mediator of lipid transport from peripheral tissues to the liver (ie, the "reverse" pathway) could restore normal endothelial function in vivo. Using assays of macrovascular and microvascular function, we found that genetically hypercholesterolemic apolipoprotein E knockout mice exhibited key endothelial impairments. Treatment of the mice for 1 week with daily intravenous bolus injections of large "empty" phospholipid vesicles, which accelerate the reverse pathway in vivo, restored endothelium-dependent relaxation, leukocyte adherence, and endothelial expression of vascular cell adhesion molecule-1 to normal or nearly normal levels. These changes occurred despite the long-standing hyperlipidemia of the animals and the persistence of high serum concentrations of cholesterol-rich atherogenic lipoproteins during the treatment. Our results indicate that dysfunctional macrovascular and microvascular endothelium in apolipoprotein E knockout mice can recover relatively quickly in vivo and that accelerated reverse lipid transport may be a useful therapy. Key Words: cell adhesion molecules Ⅲ endothelium-derived factors Ⅲ hypercholesterolemia Ⅲ leukocytes Ⅲ vasodilation I n hypercholesterolemic animals and humans, the endothelium of medium-sized muscular arteries, such as the coronary arteries, loses its ability to release biologically available nitric oxide, a vasodilator required for endotheliumdependent relaxation of vessels in response to ADP, acetylcholine, hypoxia, and other stimuli. [1][2][3][4][5][6] Furthermore, in hypercholesterolemia, the luminal surface of vascular endothelium displays abnormally high levels of P-selectin and vascular cell adhesion molecule-1 (VCAM-1). On the venous but not the arterial side, 6,7 these endothelial cell adhesion molecules mediate leukocyte rolling (tethering) and adherence (immobilization), respectively, by binding to counterreceptors on the leukocytes. 8 -10 These changes in the macrovasculature and microvasculature occur early, within 1 to 2 weeks after the onset of atherogenic hypercholesterolemia, 3,6,8 -10 well before overt atherosclerosis has developed. In humans, lowering the plasma concentration of LDL and other cholesterol-rich atherogenic lipoproteins that deliver harmful lipids into the vessel wall 11,12 has been reported to improve endothelium-dependent vasomotor regulation after several months, 4,5,13,14 although full normalization of endothelium-dependent relaxation is uncommon 4,5,13 and may require the simultaneous administration of antioxidants 15,16 or extreme measures to lower LDL levels. 17,18 Similarly, elevated plasma concentrations of soluble cell adhesion molecules seen in human hyperlipidemias respond only minimally to aggressive drug treatments to lower plasma lipid levels. 19 The therapeutic approach of LDL lowering, with or without the coadministration of antioxidants, presumably attenuates further...

Accelerated Atherosclerosis, Aortic Aneurysm Formation, and Ischemic Heart Disease in Apolipoprotein E/Endothelial Nitric Oxide Synthase Double-Knockout Mice

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The effect of phospholipid composition of reconstituted HDL on its cholesterol efflux and anti-inflammatory properties

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Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: A pathway for late-stage quality control

“…Thus, lipid peroxidation is kept within the liver, where it is safe, even beneficial (40), and away from potentially vulnerable peripheral organs. Reverse transport of oxidized or oxidizable lipids from periphery to liver could serve a similar function (9,41).…”