Decreased aortic glutathione levels may contribute to impaired nitric oxide‐induced relaxation in hypercholesterolaemia

Adachi, Takeshi; Cohen, Richard A.

doi:10.1038/sj.bjp.0703127

Cited by 30 publications

(24 citation statements)

References 31 publications

(43 reference statements)

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“…These results are in line with the results obtained from previous reports. 20,21) Treatment of atherogenic-diet rats with either low or high doses of MSC markedly lowered plasma total and LDL-cholesterol concentrations. HDL-cholesterol concentrations remained unchanged.…”

Section: Discussionmentioning

confidence: 99%

Anti-atherogenic Effects of the Methanol Extract of Sorbus Cortex in Atherogenic-Diet Rats

Sohn

Kang

Mun

et al. 2005

Biological & Pharmaceutical Bulletin

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The present study was designed to examine whether the methanol extract of Sorbus commixta cortex (MSC) could prevent the development of atherosclerosis through regulating the vascular nitric oxide (NO) and endothelin-1 (ET-1) systems in atherogenic-diet rats. Our findings show that aortic NO production as well as endothelial nitric oxide synthase (ecNOS) expression was significantly decreased in atherogenic-diet rats compared with those in the control group. Aortic ET-1 expression was augmented in rats fed an atherogenic-diet while NF-k kB p65 was upregulated. Treatment of atherogenic-diet rats with either low (100 mg/kg/d) or high (200 mg/kg/d) doses of MSC led not only to significant increases in the aortic NOS/NO system, but also to decreases in aortic ET-1 expression. The aortic expression level of NF-k kB p65 was also attenuated in atherogenic-diet rats by chronic treatment with low or high doses of MSC. Atherogenic-diet induced increases in the expression of adhesion molecules including intercellular adhesion molecules-1 (ICAM-1), vascular cell adhesion molecue-1 (VCAM-1), and E-selectin were markedly decreased by treatment with MSC. From the histopathological examination, MSC treatment was shown to lessen the thickening noted in the aortic intima and media of the atherogenic-diet rats. These results suggest that MSC affects the atherogenic process via the suppression of proinflammatory and adhesion molecules in atherogenic-diet rats, which may be, at least in part, causally related with the regulation of vasoactive systems such as the NO and ET-1 systems.

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Section: Discussionmentioning

confidence: 99%

Anti-atherogenic Effects of the Methanol Extract of Sorbus Cortex in Atherogenic-Diet Rats

Sohn

Kang

Mun

et al. 2005

Biological & Pharmaceutical Bulletin

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“…A saturated NO solution (Ϸ3 mmol/L) was prepared at 4°C and depleted of anionic oxidation products of NO with an anion exchange resin, as described previously. 18,19,22,33,34 Monoclonal SERCA2 antibody was from Affinity Bioreagents (clone IID8). Polyclonal antibody for 3-nitrotyrosine was from Upstate Biochemicals.…”

Section: Reagentsmentioning

confidence: 99%

“…17 Increased scavenging of NO by superoxide may decrease NO bioactivity; however, a few hours of incubation with antioxidants 18,19 or adenovirusmediated gene transfer of superoxide dismutase 20 fails to normalize endothelium-dependent relaxation, suggesting that a decrease in superoxide generation is not enough to immediately restore NO bioactivity in HC.…”

mentioning

confidence: 99%

Antioxidant Improves Smooth Muscle Sarco/Endoplasmic Reticulum Ca ²⁺ -ATPase Function and Lowers Tyrosine Nitration in Hypercholesterolemia and Improves Nitric Oxide–Induced Relaxation

Adachi

Matsui

et al. 2002

Circulation Research

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Abstract-Antioxidants improve endothelial function in hypercholesterolemia (HC); however, whether this includes improvement of the vascular smooth muscle response to NO is unknown. NO relaxes arteries, in part, by stimulating Ca 2ϩ uptake via sarco/endoplasmic reticulum Ca 2ϩ -ATPase (SERCA) in aortic smooth muscle, and HC impairs SERCA function and the response to NO. HC induces oxidative stress, which could impair SERCA function. To study the effect of antioxidants, which are known to improve endothelium-dependent relaxation in HC, smooth muscle SERCA activity and NO-induced relaxation were studied in rabbits fed normal chow or a 0.5% cholesterol diet for 13 weeks. The antioxidant t-butylhydroxytoluene (BHT, 1%) was mixed with the HC diet in the last 3 weeks. HC impaired acetylcholine-and NO-induced relaxation, and these were restored by BHT. After inhibiting SERCA with thapsigargin, no difference existed in NO-induced relaxation among the three groups. Reduced aortic SERCA activity in HC was restored by BHT without changing SERCA protein expression. 3-Nitrotyrosine was notably increased in the media of the HC aorta, where it colocalized with SERCA. Tyrosine-nitrated SERCA protein was immunoprecipitated in the aortas of HC rabbits, where it was decreased by BHT, and it was also detected in the aortas of atherosclerotic humans. Thus, the antioxidant reverses impaired smooth muscle SERCA function in HC, and this is correlated with the improved relaxation to NO. These beneficial effects may depend on reducing the direct effects on SERCA of reactive oxygen species that are augmented in HC. Key Words: t-butylhydroxytoluene Ⅲ nitric oxide Ⅲ sarco/endoplasmic reticulum Ca 2ϩ -ATPase Ⅲ atherosclerosis Ⅲ nitrotyrosine H ypercholesterolemia (HC) and other vascular diseases, including hypertension, 1-3 diabetes, 4,5 and hyperhomocysteinemia, 6,7 may increase oxidative stress and decrease NO bioactivity, which may be associated with promoting atherosclerosis. 8 Antioxidants, including ␤-carotine, 9 vitamin E, 9,10 vitamin C, 11 and probucol, 12,13 improve endotheliumdependent relaxation in HC. The effects of these antioxidants do not depend on lowering plasma cholesterol levels, 12,13 suggesting that oxidative stress in HC is related to vascular dysfunction. 14 However, the protective mechanism of antioxidants on NO bioactivity has not yet been elucidated.Oxidative stress may impair NO release 15 or endothelial NO synthase function, 16 although increased NO release in HC has also been reported. 17 Increased scavenging of NO by superoxide may decrease NO bioactivity; however, a few hours of incubation with antioxidants 18,19 or adenovirusmediated gene transfer of superoxide dismutase 20 fails to normalize endothelium-dependent relaxation, suggesting that a decrease in superoxide generation is not enough to immediately restore NO bioactivity in HC.Another possible factor is that oxidative stress impairs the function of target proteins of NO in aortic smooth muscle. NO activates guanylyl cyclase and relaxes arteries, and its...

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“…HC increases superoxide production, 6 and therefore increased scavenging of NO might account for the discrepancy between NO and SNP. Although long-term treatment with antioxidants improves vascular function in HC rabbit aorta, antioxidants like glutathione ester 7 or other scavengers of superoxide anion do not immediately normalize responses either to endothelium-dependent agents or to NO. Adenoviral transfection of superoxide dismutase (SOD) had no effect, 8 and extended in vivo treatment with a cell-permeable form of SOD 9 only partially improved endothelium-dependent relaxation in HC.…”

mentioning

confidence: 93%

Reduced Sarco/Endoplasmic Reticulum Ca ²⁺ Uptake Activity Can Account for the Reduced Response to NO, but Not Sodium Nitroprusside, in Hypercholesterolemic Rabbit Aorta

et al. 2001

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Background-Hypercholesterolemia (HC) impairs acetylcholine-induced relaxation but has little effect on that caused by the NO donor sodium nitroprusside (SNP), suggesting that acetylcholine releases less NO from the endothelium in HC. The relaxation to authentic NO gas, however, is also impaired in HC aortic smooth muscle, indicating an abnormal smooth muscle response. NO relaxes arteries by both cGMP-dependent and -independent mechanisms, and the response involves calcium (Ca 2ϩ ) store refilling via the sarco/endoplasmic reticulum calcium ATPase (SERCA). We studied the involvement of cGMP and SERCA in the smooth muscle response to NO and SNP in HC rabbit aorta. Methods and Results-A selective guanylyl cyclase inhibitor, 1H-[1,2,4]-oxadiazole-[4,3-a]quinoxalin-1-one, eliminated SNP-induced relaxation but only partially blocked NO-induced relaxation in both normal and HC aorta. The residual relaxation to NO was still less in HC and, in both normal and HC aorta, was abolished by concomitant administration of the SERCA inhibitor cyclopiazonic acid (CPA). In contrast, CPA did not affect SNP-induced relaxation in either normal or HC aorta. SERCA activity measured by 45 Ca 2ϩ uptake was markedly decreased in HC, although SERCA2 protein expression did not change significantly. Conclusions-These data suggest that NO-induced relaxation but not that to SNP is partially mediated by cGMPindependent Ca 2ϩ uptake into sarco/endoplasmic reticulum and that reduced sarco/endoplasmic reticulum Ca 2ϩ pump function can account for the impaired response to NO in HC. Key Words: hypercholesterolemia Ⅲ nitric oxide Ⅲ sarcoplasmic reticulum Ⅲ muscle, smooth Ⅲ calcium H ypercholesterolemia (HC) impairs endotheliumdependent relaxation but has little effect on sodium nitroprusside (SNP)-induced relaxation. 1,2 Therefore, it is widely accepted that HC impairs endothelial release of NO and that the smooth muscle response to nitric oxide (NO) is preserved. Previously, we used authentic NO gas solution and showed that the decreased relaxation to acetylcholine in rabbit 1 and mouse 3 aortic rings was mirrored by decreased relaxation to NO. The decrease in intracellular free calcium caused by NO in smooth muscle from HC aorta in primary culture is also decreased in magnitude. 1 It is not clear why the relaxation to NO and SNP is affected differently in HC aorta, but the question of whether the release and/or the response to NO is impaired is an important one from both an experimental and a therapeutic viewpoint. NO gas requires diffusion, which can be interfered with by oxygen, superoxide anion, and metals. 4 SNP can release NO by 1 electron reduction at the plasma membrane of smooth muscle cells, 5 where it might not be as susceptible as NO to scavenging. HC increases superoxide production, 6 and therefore increased scavenging of NO might account for the discrepancy between NO and SNP. Although long-term treatment with antioxidants improves vascular function in HC rabbit aorta, antioxidants like glutathione ester 7 or other scavengers of super...

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Decreased aortic glutathione levels may contribute to impaired nitric oxide‐induced relaxation in hypercholesterolaemia

Cited by 30 publications

References 31 publications

Anti-atherogenic Effects of the Methanol Extract of Sorbus Cortex in Atherogenic-Diet Rats

Anti-atherogenic Effects of the Methanol Extract of Sorbus Cortex in Atherogenic-Diet Rats

Antioxidant Improves Smooth Muscle Sarco/Endoplasmic Reticulum Ca ²⁺ -ATPase Function and Lowers Tyrosine Nitration in Hypercholesterolemia and Improves Nitric Oxide–Induced Relaxation

Reduced Sarco/Endoplasmic Reticulum Ca ²⁺ Uptake Activity Can Account for the Reduced Response to NO, but Not Sodium Nitroprusside, in Hypercholesterolemic Rabbit Aorta

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Decreased aortic glutathione levels may contribute to impaired nitric oxide‐induced relaxation in hypercholesterolaemia

Cited by 30 publications

References 31 publications

Anti-atherogenic Effects of the Methanol Extract of Sorbus Cortex in Atherogenic-Diet Rats

Anti-atherogenic Effects of the Methanol Extract of Sorbus Cortex in Atherogenic-Diet Rats

Antioxidant Improves Smooth Muscle Sarco/Endoplasmic Reticulum Ca 2+ -ATPase Function and Lowers Tyrosine Nitration in Hypercholesterolemia and Improves Nitric Oxide–Induced Relaxation

Reduced Sarco/Endoplasmic Reticulum Ca 2+ Uptake Activity Can Account for the Reduced Response to NO, but Not Sodium Nitroprusside, in Hypercholesterolemic Rabbit Aorta

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Antioxidant Improves Smooth Muscle Sarco/Endoplasmic Reticulum Ca ²⁺ -ATPase Function and Lowers Tyrosine Nitration in Hypercholesterolemia and Improves Nitric Oxide–Induced Relaxation

Reduced Sarco/Endoplasmic Reticulum Ca ²⁺ Uptake Activity Can Account for the Reduced Response to NO, but Not Sodium Nitroprusside, in Hypercholesterolemic Rabbit Aorta