Hypercholesterolemia promotes inflammation and microvascular dysfunction: role of nitric oxide and superoxide1

Stokes, Karen Y.; Cooper, Dianne; Tailor, Anitaben; Granger, D. Neil

doi:10.1016/s0891-5849(02)01015-8

Cited by 235 publications

(178 citation statements)

References 44 publications

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“…Elevated levels of ROS are thought to contribute to vasomotor dysfunction during inflammation (4,15,26). Previous studies (4,15,20) suggest that levels of ROS, including superoxide, are elevated in blood vessels after LPS.…”

Section: Discussionmentioning

confidence: 99%

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Gene transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin

Lund¹

2004

American Journal of Physiology-Heart and Circulatory Physiology

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transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin. Am J Physiol Heart Circ Physiol 287: H805-H811, 2004; 10.1152/ajpheart.00907.2003 impairs vascular function, in part by generation of reactive oxygen species. One goal of this study was to determine whether gene transfer of extracellular SOD (ECSOD) improves vascular responsiveness in LPS-treated rats. A second goal was to determine whether effects of ECSOD are dependent on the heparin-binding domain of the enzyme, which facilitates binding of ECSOD to the outside of cells. Adenoviruses containing ECSOD (AdECSOD), ECSOD with deletion of its heparin-binding domain (AdECSOD-HBD), or a control virus (AdLacZ) were injected intravenously into rats. Three days later, vehicle or LPS (10 mg/kg ip) was injected. After 24 h, vascular reactivity was examined in aortic rings in vitro. Maximum relaxation to acetylcholine was 95 Ϯ 1% (means Ϯ SE) after AdlacZ plus vehicle and 77 Ϯ 3% after AdlacZ plus LPS (P Ͻ 0.05). Responses to calcium ionophore A-23187 and submaximal concentrations of nitroprusside also were impaired by LPS. Gene transfer of ECSOD, but not AdECSOD-HBD, improved (P Ͻ 0.05) relaxation to acetylcholine and A-23187 after LPS. Maximum relaxation to acetylcholine was 88 Ϯ 3% after LPS plus AdECSOD. Superoxide was increased in aorta after LPS, and the levels were reduced after AdECSOD but not AdECSOD-HBD. LPS-induced adhesion of leukocytes to aortic endothelium was reduced by AdECSOD but not by AdECSOD-HBD. We conclude that after gene transfer in vivo, binding of ECSOD to arteries effectively decreases the numbers of adherent leukocytes and levels of superoxide and improves impaired endothelium-dependent relaxation produced by LPS. acetylcholine; adenovirus; rats; hydroethidine LPS PRODUCES IMPAIRMENT OF endothelium-dependent vascular relaxation (3,4,15). Several studies suggest that endothelial dysfunction in LPS-treated vessels may be produced, in part, by increased levels of reactive oxygen species (ROS), especially superoxide, in blood vessels (15,21). SOD, which reduces superoxide to hydrogen peroxide, improves endothelium-dependent relaxation in several pathological conditions in which superoxide is elevated in blood vessels (6, 10, 11, 18 -20, 28).Extracellular SOD (ECSOD), in contrast to other isoforms of SOD, is a secreted protein found predominantly outside of cells (12). A COOH-terminal binding domain has affinity for heparin [thus heparin-binding domain (HBD)] or sulfated proteoglycans, which facilitate binding of ECSOD to the external surfaces of many cells, including endothelial cells (12). Truncated forms of ECSOD, without HBDs or with decreased heparin-binding affinity, normally constitute a small percentage of endogenous ECSOD (12) and may, or may not, be important for vascular function. Decreases in ECSOD with high affinity for heparin, and increases in forms of ECSOD with low affinity for heparin, have been observed in atherosclerosis (12). Thus decreased function of the HBD on ECSOD may...

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Section: Discussionmentioning

confidence: 99%

“…Leukocytes produce ROS, including superoxide, and may contribute to elevated levels of oxidants in endothelium during inflammation (21,26). It is not clear, however, whether superoxide from vascular cells or leukocytes accounts for impairment of endothelial function.…”

Section: Discussionmentioning

confidence: 99%

Gene transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin

Lund¹

2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…At higher concentrations, ROS and RNS participate in the alteration of cellular phenotype from a basal state to an activated state resulting in increased inflammatory signaling and in increased ROS and RNS formation. The increase in ROS, RNS, and inflammatory signaling results in increased leukocyte and platelet activation and increased leukocyte recruitment (Patel et al 2000b;Cooper et al 2002;Stokes et al 2002a;Stokes et al 2002b). The modification of cellular phenotype and increased levels of ROS and RNS are associated with oxidative stress and vascular disease formation and progression.…”

Section: Mortality and Morbiditymentioning

confidence: 99%

“…NO availability appears to be one of the primary factors in vascular disease development. Reduced NO levels and availability is highly correlated with vascular disease (Patel et al 2000a;Stokes et al 2002b;Harrison et al 2003b;Kaysen et al 2004). …”

Section: Nitric Oxidementioning

confidence: 99%

Mechanisms of H2O2-induced oxidative stress in endothelial cells

Coyle

Martínez

Coleman

et al. 2006

Free Radical Biology and Medicine

132

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“…3,4 However, the processes involved in atherosclerosis (arteriosclerosis affecting arteries) may be somewhat different to those in arteriolosclerosis (arteriosclerosis affecting smaller arteriolar branches) 5,6 and therefore the relationship of dyslipidaemia to arteriolosclerosis is less clear. There is some evidence that hypercholesterolaemia may also cause both functional 5,7-10 and structural changes 11,12 in the peripheral microvasculature.…”

Section: Introductionmentioning

confidence: 99%

Dyslipidaemia and microvascular disease in the retina

Leung

Wang

Rochtchina

et al. 2004

Eye

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Purpose There are few data on the effect of serum lipids on microvascular disease. This study assessed the relationships between serum lipid levels and microvascular disease, as seen in the retina, among participants who attended a population-based study in Australia (n ¼ 3654, aged 49 þ years). Methods Diameters of retinal arterioles and venules were measured from digitised photographs of each participant to obtain an estimate of generalised arteriolar narrowing. Focal arteriolar narrowing, arteriovenous nicking, and retinopathy lesions (microaneurysms, haemorrhages, hard/soft exudates) were graded using a standard protocol. Fasting blood tests were performed in 89% of subjects. Adjusted means were calculated using general linear models. Logistic regression models were used to determine the odds ratios for retinal microvascular signs. Results After controlling for age, sex, body mass index, smoking, and mean arterial blood pressure, elevated high-density lipoprotein cholesterol was associated with narrower retinal arterioles (P trend ¼ 0.002) and venules (P trend ¼ 0.03) and with increased odds of generalised arteriolar narrowing (odds ratio 1.6, 95% confidence interval 1.1-2.2 for the highest vs the lowest quintile of high-density lipoprotein cholesterol). Serum triglyceride had a U-shaped relationship with venular diameter (P trend ¼ 0.003). We found no consistent pattern of association between serum total cholesterol or low-density lipoprotein cholesterol and any retinal microvascular signs. Conclusions These findings suggest that microvascular disease in the retina may result from processes distinct from dyslipidaemia.

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Hypercholesterolemia promotes inflammation and microvascular dysfunction: role of nitric oxide and superoxide1

Cited by 235 publications

References 44 publications

Gene transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin

Gene transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin

Mechanisms of H2O2-induced oxidative stress in endothelial cells

Dyslipidaemia and microvascular disease in the retina

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