Time course of 125I-labeled LDL accumulation in the healing, balloon-deendothelialized rabbit aorta.

Chang, Matthew S.; Lees, Ann M.; Lees, Robert S.

doi:10.1161/01.atv.12.9.1088

Cited by 18 publications

(20 citation statements)

References 41 publications

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“…Several recent studies have followed the time course of I 251-LDL accumulation in healing, balloon-deendothelialized rabbit aorta (41,42) and WHHL (43). Persistent LDL sequestration, which is focal and apparently extracellular, is observed in both the spontaneous WHHL and the catheterinduced lesions, despite falling levels of plasma LDL (41).…”

Section: Resultsmentioning

confidence: 99%

Delivery of Benzoporphyrin Derivative, a Photosensitizer, into Atherosclerotic Plaque of Watanabe Heritable Hyperlipidemic Rabbits and Balloon‐Injured New Zealand Rabbits

Allison

Crespo

Jain

et al. 1997

Photochem & Photobiology

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In this study we compared the plasma distribution and arterial accumulation of a photosensitizer, benzoporphyrin derivative (BPD), in two models of atherosclerosis: the spontaneous lesions of the Watanabe heritable hyperlipidemic (WHHL) rabbit and induced lesions of the balloon-injured, cholesterol-fed New Zealand white (NZW) rabbit. Selective uptake and retention of a photosensitizer by the abnormal portion of a vessel is a necessity in order for photodynamic therapy to become a successful modality for inhibition of intimal hyperplasia, selective removal of atherosclerotic tissue or imaging of diseased arteries. Liposome-based formulations were compared to freshly isolated native low density lipoprotein (LDL) and acetylated-LDL (Ac-LDL) as delivery vehicles for BPD. Plasma distribution of the photosensitizer was analyzed by KBr density gradient ultracentrifugation. Although the delivery vehicle influenced plasma distribution immediately postinjection, BPD subsequently partitioned according to the plasma concentration of the lipoproteins. Photosensitizer level in plaque and normal artery specimens was determined by ethyl acetate extraction and spectrofluorometric measurement. The measurement of BPD in normal and atherosclerotic arterial tissue demonstrated a selective accumulation in atherosclerotic tissue. Preassociation with LDL and Ac-LDL enhanced accumulation of BPD in atherosclerotic tissue when compared with normal artery (mean ratios of 2.8 and 4.1 were achieved, respectively). These results indicate that the preferential uptake of BPD by atherosclerotic plaque can be enhanced by preassociation with plasma lipoproteins, suggesting that light activation could lead to a highly selective destruction of diseased vascular tissue.

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Section: Resultsmentioning

confidence: 99%

Delivery of Benzoporphyrin Derivative, a Photosensitizer, into Atherosclerotic Plaque of Watanabe Heritable Hyperlipidemic Rabbits and Balloon‐Injured New Zealand Rabbits

Allison

Crespo

Jain

et al. 1997

Photochem & Photobiology

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“…Furthermore, in some experimental models, an intact endothelium is required for lesion initiation and development, which do not occur in adjacent areas of denudation. 16,17,18 Gross endothelial denudation, though presumably important in restenosis after balloon injury 19 and in very advanced complicated plaques, does not appear to be central to early atherogenesis. 5 A refinement of the response-to-injury hypothesis states that endothelial injuries that are insufficient to cause gross denudation but severe enough to cause functional modifications are key to atherogenesis.…”

Section: Competing Hypothesesmentioning

confidence: 99%

The Response-to-Retention Hypothesis of Early Atherogenesis

Williams

Tabas

1995

ATVB

1,228

924

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This idea is related to the lipid infiltration hypothesis, 5 which originated with Anichkov and Khalatov 28 (reviewed in References 29 and 30 29, 30). Alterations in permeability or even microscopic losses of endothelial cells in excess of those due to normal cell turnover are not mechanistically required for atherogenesis, however, because normal, healthy endothelium transports 31, 32 or "leaks" 26, 33 many molecules, including lipoproteins (reviewed in Reference 27 27). In fact, the rate of LDL entry into the normal, healthy arterial wall vastly exceeds the LDL accumulation rate. 34 Most important, seminal studies by Schwenke and Carew 35, 36 showed in vivo that the early prelesional accumulation of atherogenic lipoproteins within the arterial wall is focally concentrated in sites that are known to be prone to the later development of atheromata, but that the rates of lipoprotein entry into prelesional susceptible versus resistant sites were not different (cf Reference 2 2). These studies indicate that retention, not enhanced endothelial permeability to lipoprotein influx, is the key pathological event in this experimental model. Subsequent studies in several other animal models have demonstrated either increased 23, 24, 25, 26 or decreased 37 rates of lipoprotein entry into atherosclerosis-susceptible sites, suggesting a nonessential role for alterations in endothelial permeability. All studies agree, however, that prelesional susceptible arterial sites show enhanced retention of apoB-rich, atherogenic lipoproteins. 35, 36, 38, 39, 40, 41 We conclude that alterations in endothelial permeability, though apparently not essential to lesion development, may play a contributory role, eg, in smoking, 42 dyslipidemias 27, 37 (cf Reference 36 36), and possibly hypertension 27 (cf Reference 43 43), but only if some of the infiltrated material is retained. 35 Several other functional modifications have been documented in the endothelial layer in vivo during atherogenesis, but these occur comparatively late. For example, in rabbits, cell adhesion molecules, 44 the earliest known being vascular cell adhesion molecule-1 (VCAM-1), are expressed by endothelial cells that overlie lesions, but only after more than 4 days of severe hypercholesterolemia and resultant foam cell formation. 45 In contrast, lipoprotein retention and aggregation are detectable within minutes to hours after the onset of hypercholesterolemia. 31, 36, 41, 46 Furthermore, atherogenic lipoproteins and their components have been shown to regulate endothelial expression of cell-adhesion molecules. 12, 47, 48, 49 The most straightforward conclusion is that the earliest known endothelial changes during atherogenesis in vivo, such as VCAM-1 expression, cannot be a cause, and are likely to be a consequence, of the initial retention of lipoproteins within the arterial wall (see "Future Directions").

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“…Fractional rates of degradation are in fact lower under these conditions possibly due to saturation and down-regulation of LDL receptors in arterial cells. Likewise, after vascular injury a persis- tent increase in levels of intact LDL is seen in the neointima (21,22).…”

Section: Discussionmentioning

confidence: 99%

Increased low density lipoprotein degradation in aorta of irradiated mice is inhibited by preenrichment of low density lipoprotein with α-tocopherol

Krauss

Chu

Gong

et al. 2000

Journal of Lipid Research

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We previously reported that upper thoracic exposure to ionizing radiation (IR) accelerates fatty streak formation in C57BL/6 mice and that such effects are inhibited by overexpression of the antioxidant enzyme CuZn-superoxide dismutase (SOD). Notably, IR-accelerated lesion formation is strictly dependent on a high fat diet (i.e., atherogenic lipoproteins) but does not involve alterations in circulating lipid or lipoprotein levels. We thus proposed that IR promotes changes in the artery wall that enhance the deposition of lipoprotein lipids. To address this hypothesis, we examined the effects of IR on aortic accumulation and degradation of low density lipoproteins (LDL). Ten-week-old C57BL/6 mice were exposed to a single (8-Gy) dose of 60 Co radiation to the upper thoracic area or were sham irradiated (controls) and were then placed on the high fat diet. Five days postexposure, the mice received either 125 I-labeled LDL ( 125 I-LDL) (which was used to measure intact LDL) or 125 Ilabeled tyramine cellobiose ( 125 I-TC)-LDL (which was used to measure both intact and cell-degraded LDL) via tail vein injection. On the basis of trichloroacetic acid (TCA)-precipitable counts in retroorbital blood samples, у 95% of donor LDL was cleared within 24 h and there were no differences in time-averaged plasma concentrations of the two forms of LDL among irradiated and control mice. Aortic values increased markedly within the first hour and thereafter exhibited a slow increase up to 24 h. There were no differences between irradiated and control mice at 1 h, when values primarily reflected LDL entry, but a divergence was observed thereafter. At 24 h, 125 I-TC-associated counts were 1.8-fold higher in irradiated mice ( P ϭ 0.10). In contrast, 125 I-LDLassociated counts were 30% lower in irradiated mice ( P Ͻ 0.05), suggesting that most of the retained 125 I-TC was associated with LDL degradation products. Consistent with the proposed involvement of oxidative or redox-regulated events, IR-induced LDL degradation was lower in SODtransgenic than wild-type mice ( P Ͻ 0.05). The importance of LDL oxidation was suggested by observations that IRinduced LDL degradation was significantly reduced by preenriching LDL with ␣ -tocopherol. On the basis of these results, we propose that IR elicits SOD-inhibitable changes in the artery wall that enhance LDL oxidation and degradation leading to the deposition of LDL-borne lipids. These studies provide additional support for the role of oxidation in lipoprotein lipid deposition and atherogenesis and sug-gest that IR promotes an arterial environment that stimulates this process in vivo.

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Time course of 125I-labeled LDL accumulation in the healing, balloon-deendothelialized rabbit aorta.

Cited by 18 publications

References 41 publications

Delivery of Benzoporphyrin Derivative, a Photosensitizer, into Atherosclerotic Plaque of Watanabe Heritable Hyperlipidemic Rabbits and Balloon‐Injured New Zealand Rabbits

Delivery of Benzoporphyrin Derivative, a Photosensitizer, into Atherosclerotic Plaque of Watanabe Heritable Hyperlipidemic Rabbits and Balloon‐Injured New Zealand Rabbits

The Response-to-Retention Hypothesis of Early Atherogenesis

Increased low density lipoprotein degradation in aorta of irradiated mice is inhibited by preenrichment of low density lipoprotein with α-tocopherol

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