Exposure to oxidized low-density lipoprotein in vivo enhances intimal thickening and selectively impairs endothelium-dependent dilation in the rabbit

Ke, Matthys; Ce, Van Hove; Mm, Kockx; Lj, Andries; N, Van Osselaer; Ag, Herman; Bult, Hidde

doi:10.1016/s0008-6363(97)00202-2

Cited by 16 publications

(10 citation statements)

References 32 publications

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“…On the other hand, galactose-induced deficits in relaxation of aortas were prevented by aldose reductase inhibition [21]. Moreover, polyol accumulation and osmotic stress lead to compromised integrity of cell membranes [36], which facilitates non-receptor-mediated uptake of oxidized low-density lipoproteins which are implicated in intimal thickening [37,38]. Our study also morphologically confirmed that the intimal thickening of coronary arteries of galactosaemic dogs can be prevented by an aldose reductase inhibitor.…”

Section: Discussionsupporting

confidence: 78%

An aldose redutase inhibitor prevents the intimal thickening in coronary arteries of galactose-fed beagle dogs

et al. 1999

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Macrovascular complications such as myocardial infarction, angina pectoris and cerebrovascular accidents are the major causes of mortality in diabetic patients [1,2]. Although the maintenance of a good glycaemic control for a long period can decrease the risk of the development of diabetic microangiopathy [3], the development of diabetic macroangiopathy cannot be prevented by glycaemic control [3,4]. Therefore, it is very important to establish the pathogenesis of diabetic macroangiopathy.Various hypotheses including increased polyol pathway activity, protein kinase C (PKC) activation, increased oxidative stress and enhanced non-enzymatic glycation have been implicated in the pathogenesis of diabetic microangiopathy such as retinopathy, nephropathy and neuropathy [5,6]. Hyperglycaemia-induced metabolic alterations could also contribute to the development of diabetic macroangiopathy. Although the importance of the latter three metabolic deficits in the pathogenesis of diabetic macroangiopathy have been investigated precisely [7±12], the relation between polyol pathway hyperactivity and diabetic macroangiopathy remains unclear. Diabetologia (1999) Abstract Aims/hypothesis. Although increased polyol pathway activity has been implicated in the pathogenesis of diabetic microangiopathy, the relation with diabetic macroangiopathy remains unclear. Galactose feeding is known to stimulate the polyol pathway and to develop abnormalites similar to those in diabetic microangiopathy. Our study was conducted to investigate whether an activation of polyol pathway by long-term treatment with galactose produced morphological changes in coronary arteries of dogs and the effect of an aldose reductase inhibitor, epalrestat, was also studied. Methods. Dogs received either normal chow or chow containing 30 % galactose with or without epalrestat given orally (20 or 50 mg × kg ±1 ). After 44 months, morphometric analyses of coronary arteries were carried out and the galactitol contents in aortas were measured.Results. The ratio of areas of the intimal layer to those of the medial layer, an indicator of intimal thickening, was statistically significantly increased in galactosefed dogs compared with control dogs. Galactose-fed dogs had a remarkable accumulation of galactitol in their aortas. These morphological and biochemical deficits were reduced by treatment with epalrestat. Conclusion/interpretation. This report morphologically shows diabetes-like macrovascular abnormalities in galactosaemic animals, suggesting that polyol pathway hyperactivity is closely related to the development of diabetic macroangiopathy, which could be prevented by aldose reductase inhibition. [Diabetologia (1999

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Section: Discussionsupporting

confidence: 78%

An aldose redutase inhibitor prevents the intimal thickening in coronary arteries of galactose-fed beagle dogs

et al. 1999

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“…LDL has been reported to inhibit the ability of blood vessels to relax [34], to induce a further contraction in vessels pretreated with contractile agonists [35], and to make vessels more prone to vasospasm in response to contractile stimuli [36]. However, no contraction-inducing agonists were used in this study, and no apparent contraction was observed upon addition of LDL.…”

Section: Discussionmentioning

confidence: 87%

Two-photon microscopy of aorta fibers shows proteolysis induced by LDL hydroperoxides

Parasassi

Durbin

et al. 2000

Free Radical Biology and Medicine

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Abstract-Oxidatively modified LDL mimics several aspects of atherogenesis. In this disease, degradation of the matrix proteins' network also occurs. By a new morphological ex vivo approach, not requiring sample processing, we explored the relationship between the degradation of matrix protein and oxidatively modified LDL. Two-photon excitation fluorescence microscopy images of fresh cross-section rings of rat aorta, acquired while the sample was maintained in a glucose-and oxygen-supplemented buffer, showed straight, parallel, thick, long extracellular matrix proteins. Traditional microscopic examination, requiring sample fixation and staining, shows smaller and curved fibers. Instead, we observed curved and broken fibers after a 30-min incubation of aorta with either LDL containing lipid hydroperoxides, or tert-butyl-hydroperoxide. The adhesion of LDL to the endothelium and its internalization was directly visualized by using a lipid fluorophore. The damage to aorta matrix proteins induced by LDL and tert-butylhydroperoxide was fully prevented by antioxidants, such as ascorbate or Trolox C, or inhibitors of proteases. The image spectroscopy of the fibers' autofluorescence (polarization and lifetime) revealed an increased mobility of the fluorescent cross-link in fibers. Damaged matrix proteins were also imaged in aorta samples from apolipoprotein E knock-out mice. Our ex vivo images directly visualized the activation of a fast redox-sensitive proteolytic process in the arterial wall triggered by lipid hydroperoxides in LDL.

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“…OxLDL is toxic to endothelial cells [14]and causes the production of superoxide anions by endothelial cells [15], an effect which may augment or accelerate endothelial dysfunction [16, 17, 18]. Furthermore, blood vessels exposed to OxLDL following injury show enhanced intimal thickening [19], confirming a role for OxLDL in the long-term sequelae of vascular injury. Endothelial cells are capable of internalizing minimally oxidized LDL (mmLDL), which corresponds to a physiological level of LDL oxidation.…”

Section: Introductionmentioning

confidence: 99%

Cells Derived from Regenerated Endothelium of the Porcine Coronary Artery Contain More Oxidized Forms of Apolipoprotein-B-100 without a Modification in the Uptake of Oxidized LDL

et al. 2003

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Increased accumulation of lipoproteins and cholesterol within cells from regenerated endothelium may be responsible for their reported dysfunction. This study compared the presence and uptake of oxidized forms of low-density lipoprotein (LDL) in cells derived from native and regenerated endothelium. Four weeks after balloon denudation, primary cultures of native and regenerated endothelial cells were prepared from porcine coronary arteries. Regenerated endothelium stained more strongly using an antibody against oxidized lipoproteins. The increase in oxidized forms of apolipoprotein-B-100 exhibited by cells from regenerated endothelium was not due to an increase in extracellular-induced oxidation of native LDL, measured as the production of thiobarbituric-acid-reactive substances, being identical in both cell types. Intracellular cholesterol and cholesterol ester content were unchanged in regenerated cells. Using flow cytometry, accumulation of oxidized LDL was investigated further by quantifying the uptake of a mildly oxidized preparation of 1,1’-dioctadecyl-3,3,3’,3-tetramethyl-indocarbocyanine perchlorate-labelled LDL. The parameters of uptake, EC₅₀ and E_max, were not different between cells from native and regenerated endothelium suggesting that the number of LOX-1 receptors was identical in the two cell types. Moreover, a negative correlation between the increased uptake of acetylated LDL and decreased cGMP production in response to bradykinin was observed in cells from regenerated endothelium. Thus, the increased incorporation of modified LDL and their intracellular oxidation could be responsible for the alteration in NO production. The presence of oxidized forms of LDL may be a marker of endothelium regeneration and could be involved in the endothelial dysfunction of pig coronary arteries 4 weeks after balloon denudation.

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Exposure to oxidized low-density lipoprotein in vivo enhances intimal thickening and selectively impairs endothelium-dependent dilation in the rabbit

Abstract: Our results show for the first time that local vascular exposure to oxLDL in vivo promotes intimal thickening and inhibits endothelium-dependent dilation, thereby supporting an active role for oxLDL in the morphological and functional changes observed in atherosclerotic blood vessels.

Cited by 16 publications

References 32 publications

An aldose redutase inhibitor prevents the intimal thickening in coronary arteries of galactose-fed beagle dogs

An aldose redutase inhibitor prevents the intimal thickening in coronary arteries of galactose-fed beagle dogs

Two-photon microscopy of aorta fibers shows proteolysis induced by LDL hydroperoxides

Cells Derived from Regenerated Endothelium of the Porcine Coronary Artery Contain More Oxidized Forms of Apolipoprotein-B-100 without a Modification in the Uptake of Oxidized LDL

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