Inhibition of EDRF Release by Native Low-Density Lipoprotein from Cultured Porcine Endothelial Cells Through Intracellular Mechanisms

Ezaki, Masanori; Ikeda, Masahiko; Tomita, Isao; Tomita, Takako

doi:10.1097/00005344-199410000-00005

Cited by 9 publications

(5 citation statements)

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“…In vitro studies suggest that this is due to enhanced inactivation [51,52] and/or reduced synthesis of NO [53]. The result is reduced formation of cGMP in vascular smooth muscle cells [21,54]. A study looking at the effects of hypochlorite-modified LDL [24] also showed an inhibition of cGMP in human umbilical endothelial cells in a time-and dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Chylomicron-remnant-like particles inhibit the basal nitric oxide pathway in porcine coronary artery and aortic endothelial cells

et al. 2003

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The effects of chylomicron remnants on the activity of basally produced nitric oxide (NO) from porcine coronary artery rings and porcine aortic endothelial cells were studied by investigating the effects of chylomicron-remnant-like particles (CMR-LPs) containing porcine apolipoprotein E on the vessel tone of porcine coronary arteries and on cGMP release by aortic endothelial cells. CMR-LPs were oxidized by incubation with CuSO(4) (10 microM) for 18 h at 37 degrees C. N (omega)-nitro-L-arginine (L-NOARG) and oxidized CMR-LPs (oxCMR-LPs), but not native CMR-LPs, increased the vessel tone of static porcine coronary artery rings (increase in tone as a percentage of the tone induced by depolarizing Krebs-Henseleit solution: L-NOARG, 14.24 +/- 2.09; oxCMR-LPs, 4.98 +/- 0.88; and native CMR-LPs, 0.47 +/- 0.21). L-NOARG, endothelium removal and oxCMR-LPs also all significantly increased the maximum relaxation of the vessels to S -nitroso- N -acetyl-DL-penicillamine. In addition, oxCMR-LPs reduced the amounts of cGMP released by porcine aortic endothelial cells into the culture medium from 116 +/- 12.0 to 84.2 +/- 11.6 fmol/microg of cellular protein, mimicking the effects of L-NOARG. These results indicate that oxCMR-LPs, but not native CMR-LPs, inhibit the activity, production or release of NO from unstimulated porcine coronary and aortic endothelial cells. oxCMR-LPs mimicked the addition of L-NOARG and endothelium removal in these experimental systems, suggesting that the lipoproteins were interfering with the L-arginine/NO pathway. This study provides further evidence to support a role of chylomicron remnants in the development of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Chylomicron-remnant-like particles inhibit the basal nitric oxide pathway in porcine coronary artery and aortic endothelial cells

et al. 2003

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“…An increased breakdown of NO by oxygen-containing free radicals, such as superoxide anion, hydroxyl radical, or H 2 O 2 , has also been suspected in hypercholesterolemic or atherosclerotic animal models, [38][39][40] and endothelium-dependent vasodilation was reported to be improved by SOD. 41 However, the inability of SOD to antagonize inhibition of endothelium-derived relaxing factor production by cholesterol oxide-containing oxidized LDLs 36,42 and to correct the altered endothelium-dependent relaxation in patients with hypercholesterolemia. 43 did not support the concept of enhanced inactivation of NO by anion superoxide in 7-ketocholesterol-treated cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition by Cholesterol Oxides of NO Release From Human Vascular Endothelial Cells

Deckert

Brunet

Lantoine

et al. 1998

ATVB

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Abstract-Recent studies have demonstrated that, unlike cholesterol, cholesterol oxidized at position 7 can reduce the maximal endothelium-dependent relaxation of isolated rabbit aortas (Circulation. 1997;95:723-731). The aim of the current study was to determine whether cholesterol oxides reduce the release of nitric oxide (NO) from human umbilical vein endothelial cells (HUVECs). The amount of NO released by histamine-stimulated HUVECs was determined by differential pulse amperometry using a nickel porphyrin-and Nafion-coated carbon microfiber electrode. The effects of cholesterol (preserved from oxidation by butylated hydroxytoluene), 7-ketocholesterol, 7␤-hydroxycholesterol, 5␣,6␣-epoxycholesterol, 19-hydroxycholesterol (60 g/mL), and ␣-lysophosphatidylcholine (10 g/mL) were compared. Pretreatment of HUVECs with cholesterol, 5␣,6␣-epoxycholesterol, or 19-hydroxycholesterol did not alter histamineactivated NO production. In contrast, pretreatment with 7-ketocholesterol or 7␤-hydroxycholesterol significantly decreased NO release. The inhibitory effect of 7-ketocholesterol was time and dose dependent and was maintained in the presence of L-arginine. In the absence of serum, lysophosphatidylcholine also reduced NO production. In ionomycin-stimulated cells, pretreatment with 7-ketocholesterol did not inhibit NO release. These results demonstrate that cholesterol derivatives oxidized at the 7 position, the main products of low density lipoprotein oxidation, reduce histamine-activated NO release in HUVECs. Such an inhibitory effect of cholesterol oxides may account, at least in part, for the ability of oxidized low density lipoprotein to reduce the endothelium-dependent relaxation of arteries. Key Words: human endothelial cells Ⅲ cholesterol oxides Ⅲ histamine Ⅲ NO production T he endothelium of blood vessels regulates vascular tone by releasing endothelium-derived relaxing and contracting factors.1-3 In particular, it has now been clearly established that the endothelium-dependent relaxation of arteries induced by acetylcholine or histamine involves the release of endothelium-derived relaxing factor, 1,4 identified as NO. 5,6 Recent studies have demonstrated that alterations in vascular reactivity can be associated with cardiovascular disorders [7][8][9][10] and that arteries from hypercholesterolemic and atherosclerotic patients exhibit marked attenuation of endothelium-dependent relaxation. 7,11,12 Although the impairment of arterial relaxation at an early stage of the atherosclerotic process may constitute a crucial step in disease progression, the related molecular mechanisms remain unclear. Several studies have demonstrated that LDLs, rather than native LDLs, can mimic the impairment of arterial relaxation observed in hyperlipidemia. [13][14][15][16] Whereas in some previous studies the inhibition of endothelium-dependent relaxation was attributed to LPC, 14,15,17 other studies did not support this view. 16,18 In particular, no significant relationship between the LPC content of LDLs and their ability to reduc...

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“…(1 mg protein ml-') or oxidized LDL (50 lug protein ml-1) completely inhibited cGMP accumulation in target porcine smooth muscle cells induced by the eluate from endothelial cell columns stimulated with thrombin, bradykinin or A23187 (Ezaki et al 1994). These latter findings are consistent with other observations in porcine aortic endothelial cells, where intracellular cGMP levels that had been increased by bradykinin or A23187 were apparently reduced by native LDL (-10 and -80 %, respectively) without alteration of sodium nitroprusside (SNP, an NO donor)-induced increases in cGMP accumulation (Pohl et al 1995).…”

Section: Introductionmentioning

confidence: 92%

“…In addition to its chemical interactions with NO, LDL and its oxidized components have been shown to modulate cellular signalling pathways, such as G-proteins (Liao, 1994) and protein kinase C (see Ozer, Palozza, Boscoboinik & Azzi, 1993). Short-term (-1 h) effects of pathophysiologically relevant concentrations of native and oxidized LDL (-50-100 jug protein ml-'; Reichl, 1994) on NO synthesis in cultured endothelial cells have been examined by assaying the stimulatory effect of endotheliumderived NO on the activity of purified soluble guanylyl cyclase (sGC) or cGMP accumulation within the endothelium or detector cells expressing sGC (Galle et al 1991;Chin et al 1992;Mitchell, Warner, Huang, Forstermann & Murad, 1992;Ezaki, Ikeda, Tomita & Tomita, 1994;Pohl, Heydari & Galle, 1995). In bovine aortic endothelial cells, both native and oxidized LDL inactivated endothelium-derived NO and impaired NO-mediated cGMP generation, while bradykinin-stimulated synthesis of NO was unaltered (Galle et al 1991).…”

Section: Introductionmentioning

confidence: 99%

Modulation of vascular tone by low density lipoproteins: effects on L‐arginine transport and nitric oxide synthesis

Jay¹,

Chirico²,

Siow³

et al. 1997

Experimental Physiology

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SUMMARYLow density lipoprotein (LDL) plays an important role in atherogenesis. Focal accumulation within the arterial intima of excess amounts of cholesterol-rich LDL leads to the migration and recruitment of monocytes, which then differentiate into macrophages after taking up large amounts of oxidatively modified LDL via their scavenger receptors and become lipid-laden 'foam cells' within the subendothelial space. It is generally accepted that oxidized LDL and hyperlipidaemia impair endothelial-dependent vascular relaxation, yet the existing literature on the effects of oxidatively modified LDL on endothelium-derived nitric oxide (NO) and prostacyclin (PGI2) release is inconclusive, since oxidized LDL has been reported to enhance or reduce NO and PGI2 production. Our studies using cultured human endothelial and smooth muscle cells have established that basal rates of L-arginine (NO precursor) transport, NO and PGI2 production and soluble guanylyl cyclase activity are unaffected by pretreatment (for 1 or 24 h) with native LDL, or with mildly or highly oxidized LDL. In contrast, highly oxidized LDL inhibited histamine-stimulated release of NO and PGI2 from human endothelial cells and induced an adaptive increase in the level of intracellular glutathione in human smooth muscle cells, a response which was prevented by the chain-breaking antioxidant x-tocopherol. Although initial rates of L-arginine transport and basal NO and PGI2 release from human endothelium are unaffected by oxidized LDL, agonist-stimulated release of these vasodilators is markedly attenuated. Elucidation of the mechanisms regulating these responses and their sensitivity to dietary antioxidants could lead to alternative strategies for reducing atherogenesis.

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Inhibition of EDRF Release by Native Low-Density Lipoprotein from Cultured Porcine Endothelial Cells Through Intracellular Mechanisms

Cited by 9 publications

References 0 publications

Chylomicron-remnant-like particles inhibit the basal nitric oxide pathway in porcine coronary artery and aortic endothelial cells

Chylomicron-remnant-like particles inhibit the basal nitric oxide pathway in porcine coronary artery and aortic endothelial cells

Inhibition by Cholesterol Oxides of NO Release From Human Vascular Endothelial Cells

Modulation of vascular tone by low density lipoproteins: effects on L‐arginine transport and nitric oxide synthesis

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