The effect of oxygen on the development of atherosclerosis in WHHL rabbits

Okamoto, Ryozo; Hatani, Makoto; Tsukitani, Manabu; Suehiro, Atsuo; Fujino, Motohiro; Imai, N.; Takano, Shinji; Watanabe, Yoshio; Fukuzaki, Hisashi

doi:10.1016/0021-9150(83)90070-9

Cited by 28 publications

(18 citation statements)

References 18 publications

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“…Moreover, SMCs of 2 different species accumulated lipid more efficiently at 2% O 2 than at 21% O 2 (online Figure II and Figure 2). This observation corresponds with previous reports showing that hypoxic stress stimulates lipid accumulation by SMCs in vivo 33 and in vitro. 34 On the basis of lipid extracted from SMCs, esterified cholesterol, the most prominent component accumulated in the atheromatous lesion, 31 has been shown to accumulate under hypoxia (Figure 3).…”

Section: Discussionsupporting

confidence: 79%

Lipid Accumulation in Smooth Muscle Cells Under LDL Loading Is Independent of LDL Receptor Pathway and Enhanced by Hypoxic Conditions

Wada

Sugiyama²,

Yamamoto³

et al. 2002

ATVB

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Objective-The effect of a variety of hypoxic conditions on lipid accumulation in smooth muscle cells (SMCs) was studied in an arterial wall coculture and monocultivation model. Methods and Results-Low density lipoprotein (LDL) was loaded under various levels of oxygen tension. Oil red O staining of rabbit and human SMCs revealed that lipid accumulation was greater under lower oxygen tension. Cholesterol esters were shown to accumulate in an oxygen tension-dependent manner by high-performance liquid chromatographic analysis. Autoradiograms using radiolabeled LDL indicated that LDL uptake was more pronounced under hypoxia. This result holds in the case of LDL receptor-deficient rabbit SMCs. However, cholesterol biosynthesis and cellular cholesterol release were unaffected by oxygen tension. Many studies have been performed in an effort to elucidate the mechanisms of atherogenesis, including studies in animal models such as the Watanabe heritable hyperlipidemic rabbit, apoE-deficient mice, and various diet-induced hyperlipoproteinemic animal models as well as studies in various human subjects with primary and secondary hyperlipoproteinemia. These studies have revealed a transfer of LDL into the arterial wall, 3,4 the recruitment of monocytes, 5 and the proliferation of SMCs 6 as critical steps in lesion progression. However, direct in vivo evidence for the uptake of LDL or "modified LDL" leading to cellular cholesteryl ester accumulation is still awaited. A good in vitro model system of atherogenesis would enable investigation of the accumulation process, including the mechanisms of LDL modification and uptake by monocyte-derived macrophages. Such a system would provide a powerful tool for the screening of potential compounds to inhibit certain crucial atherogenic steps. Conclusions-HypoxiaThe accumulation of cholesteryl esters leads to the formation of the foam cells that are abundantly found in atheromatous lesions, the cytoplasm of which is filled with cholesteryl esters and tests positively for lipid staining, such as with oil red O. Foam cells also exhibit positive liquid crystal birefringence of cholesteryl esters and observably contain homogeneous electron-dense spheres on electron microscopy. 7 To study the in vivo mechanism of foam cell formation, we developed a system that effectively mimics the arterial cell wall structure by cultivating rabbit arterial SMCs (RASMCs) and rabbit arterial endothelial cells (RAECs) in layers, to which human peripheral monocytes are added and cocultivated for an additional 1 to 2 weeks. 8 On the addition of copper-oxidized or acetylated LDL at a concentration of 30

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Section: Discussionsupporting

confidence: 79%

Lipid Accumulation in Smooth Muscle Cells Under LDL Loading Is Independent of LDL Receptor Pathway and Enhanced by Hypoxic Conditions

Wada

Sugiyama²,

Yamamoto³

et al. 2002

ATVB

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“…The profile of lipid accumulation in hypoxic cells with HRS in our study is similar to that in aortic atheroma under hypoxic conditions in Kjeldsen's report. We previously reported that in the WHHL rabbit systemic hypoxia aggravated aortic atherosclerosis without causing a further increase in the plasma cholesterol level [23]. Our previous in vivo study and the present in vitro study suggested that enhanced lipid accumulation in the arterial wall by systemic hypoxia is produced not through the increased plasma lipid levels but through the direct effect of hypoxia on the tissue.…”

Section: Resultssupporting

confidence: 50%

Effect of Hypoxia on Lipid Accumulation in Cultured Fibroblasts from Normal Rabbit and Watanabe Heritable Hyperlipidemic Rabbit

Tsukitani

Okamoto

Ishikawa

et al. 1987

J. Clin. Biochem. Nutr.

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SummaryWe studied the effect of hypoxia on lipid accumulation in cultured Fibroblasts from normal rabbits (normal fibroblasts) and in low density lipoprotein (LDL) receptor-negative fibroblasts from WHHL (Watanabe heritable hyperlipidemic) rabbits (WHHL fibroblasts). These cells were incubated in medium with normolipemic rabbit serum (NRS) or hyperlipemic rabbit serum (HRS). The cells were incubated in a humidified atmosphere of either 20% O2, 75% N2, and 5% CO2 (control cells) or 2% O2, 93% N2, and 5 % CO2 (hypoxic cells).After 48 h incubation of normal fibroblasts in medium with 20/ NRS, free fatty acid (FFA) levels were increased slightly and the triglyceride (TG) level markedly in hypoxic cells. In the medium with 20% HRS, in addition to the increased FFA and TG levels, the free cholesterol level was increased slightly and the esterified cholesterol level markedly in hypoxic cells. Moreover, in WHHL fibroblasts, which lack LDL receptors, cellular lipid accumulation was also observed after 48 h incubation in the medium with 20% HRS, and hypoxic incubation enhanced the cellular cholesterol and TG accumulation, as in normal fibroblasts.These results suggest that under hyperlipemic conditions, non LDL receptor-mediated uptake of lipoproteins plays a major role in cellular lipid deposition and that tissue hypoxia promotes lipid accumulation in peripheral cells by the LDL receptor-independent mechanisms.

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“…In this context, it has long been postulated that systemic hypoxia may be an important cause of atherosclerosis [20,21]. First, animal models have shown that chronic hypoxia might lead to the evolution of atherosclerotic lesions [22,23]. Secondly, cell culture experiments performed under hypoxic and normoxic conditions have suggested numerous mechanisms by which hypoxia might provoke vascular remodelling [24].…”

Section: Discussionmentioning

confidence: 99%

Changes in extracranial arteries in obstructive sleep apnoea

Schulz

Seeger²,

Fegbeutel³

et al. 2005

European Respiratory Journal

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Obstructive sleep apnoea (OSA) is linked with increased cardiovascular morbidity and mortality, possibly through an enhancement of atherosclerotic vascular changes. Up to now, however, only a few studies have tried to evaluate the occurrence of atherosclerosis in patients with OSA.In the present study, ultrasonography of the large extracranial vessels was performed in a group of consecutively admitted OSA patients (n535) and a control group of non-OSA patients (n535). Common carotid artery-intima media thickness (CCA-IMT) was measured at the far wall of both proximal carotid arteries. Furthermore, the presence of plaques and stenoses of the extracranial vessels was determined. All measurements were carried out blinded to the status of the patients.In the OSA group, CCA-IMT was significantly increased when compared with the non-OSA patients and was related to the degree of nocturnal hypoxia. Additionally, the formation of plaques was more pronounced and extracranial vessel stenosis was more common in the OSA patients.In conclusion, these findings are in favour of an independent influence of obstructive sleep apnoea on atherosclerotic changes of the arterial wall, and represent further strong arguments for obstructive sleep apnoea being a risk factor on its own for the emergence of cardiovascular disease.

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The effect of oxygen on the development of atherosclerosis in WHHL rabbits

Cited by 28 publications

References 18 publications

Lipid Accumulation in Smooth Muscle Cells Under LDL Loading Is Independent of LDL Receptor Pathway and Enhanced by Hypoxic Conditions

Lipid Accumulation in Smooth Muscle Cells Under LDL Loading Is Independent of LDL Receptor Pathway and Enhanced by Hypoxic Conditions

Effect of Hypoxia on Lipid Accumulation in Cultured Fibroblasts from Normal Rabbit and Watanabe Heritable Hyperlipidemic Rabbit

Changes in extracranial arteries in obstructive sleep apnoea

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