Inactivation of endothelial derived relaxing factor by oxidized lipoproteins.

Chin, Jane H.; Azhar, Salman; Hoffman, Brian B.

doi:10.1172/jci115549

Cited by 425 publications

(162 citation statements)

References 41 publications

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“…Conversely, accumulation of the lipophilic NO in fatty streaks, serving as a depot for sustained release, could explain the unaltered or even increased E. when higher concentrations of the gas were injected into the bath. Taken together, the shift of the responses to authentic NO, but not to SIN-1, confirms suggestions that fatty streaks (Jayakody et al, 1987;Verbeuren et al, 1990), oxidized lipoproteins (Jacobs et al, 1990;Galle et al, 1991;Chin et al, 1992) (Kruth, 1985;Verbeuren et al, 1986b;Freiman et al, 1986;Jayakody et al, 1987). Indeed, focal endothelial denudation could explain the decreased amplitude, but would be difficult to reconcile with the shift of the ACh curves in organ chamber as well as bioassay.…”

Section: Fatty Streaks and Vascular Reactivitysupporting

confidence: 70%

Influence of chronic treatment with a nitric oxide donor on fatty streak development and reactivity of the rabbit aorta

Bult

Meyer

Herman

1995

British J Pharmacology

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1 The influence of chronic treatment with molsidomine, pro-drug of the nitric oxide (NO) donor, 3-morpholino-sydnonimine (SIN-1), on fatty streak development and release of NO and prostacyclin (PGI2) was studied in the aorta of normal and cholesterol-fed rabbits. 2 Groups of 10 rabbits received standard diet (150g day-'), or diets with 0.3% cholesterol, with 0.02% molsidomine or with the combination of cholesterol and molsidomine for 16 weeks. Lesion area and thickness, maximum change in isometric force (E.,,.) and sensitivity (-log EC3. or pD2) to constricting and relaxing agonists were assessed in segments of arch, thoracic and abdominal aorta. Bioassay was used to assess NO release. 3 Cholesterol-induced fatty streaks tapered off towards the abdominal aorta. Area, thickness, weight and cholesterylester content of the lesions were augmented by the NO donor, whereas the hypercholesterolaemia remained unchanged. The exacerbation was attributed to co-release of superoxide anion from the sydnonimine. 4 As fatty streaks progressed, amplitude and pD2 of acetylcholine (ACh)-induced relaxations decreased, whereas cyclic GMP and cyclic AMP second messenger systems were not influenced, since Em., and sensitivity to SIN-1 and forskolin remained unchanged. However, extensive lesions apparently trapped some NO, as the pD2 of authentic NO decreased. 5The fatty streaks curtailed the biosynthesis of PGI2 and the overflow of NO from the perfused thoracic aorta. The latter defect was not restored by L-arginine and appears to be consistent with a functional change of the endothelial muscarinic receptors. 6 The NO donor desensitized the aorta to cyclic GMP-mediated -relaxations (ACh, SIN-1 and NO), without affecting cyclic AMP-mediated relaxation to forskolin or constrictor responses to phenylephrine and 5-hydroxytryptamine. 7 The drug also suppressed the ACh-induced overflow of NO, without changing PGI2 release. This selective reduction of endothelial NO release and the desensitization of cyclic GMP-mediated relaxations occurred independently of fatty streak formation. 8 The results indicate that chronic exposure to exogenous NO downregulates endothelial NO release and cyclic GMP-mediated relaxations, and provide evidence for the existence of negative feed-back regulations of the L-arginine NO pathway under in vivo conditions.

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Section: Fatty Streaks and Vascular Reactivitysupporting

confidence: 70%

Influence of chronic treatment with a nitric oxide donor on fatty streak development and reactivity of the rabbit aorta

Bult

Meyer

Herman

1995

British J Pharmacology

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“…12 In this context, it has been shown that hypercholesterolemia reduces the bioavailability of nitric oxide: Potential mechanisms include reduced availability of L-arginine, downregulation of the guanosine Gi␣ subunit that mediates nitric oxide activation, reduced expression of nitric oxide synthase, and inactivation of nitric oxide by superoxide anions or oxidized lipoproteins. [13][14][15][16] Careful inspection of Figure 4 reveals nonsignificant impairment of endotheliumindependent dilation, which worsens in type 2DϩH similarly to endothelium-dependent dilation. The implication is that at least part of the mechanism involves the activation of cGMP in vascular smooth muscle.…”

Section: Discussionmentioning

confidence: 99%

Vascular Structural and Functional Changes in Type 2 Diabetes Mellitus

et al. 2002

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Background-To further investigate vascular morphology and function in type 2 (non-insulin-dependent) diabetes mellitus (type 2D), small arteries were examined in vitro from carefully defined cohorts of patients with or without concomitant hypertension and the results compared with those from selected normotensive nondiabetic control subjects and a group of untreated patients with essential hypertension (EH). Methods and Results-Blood vessels were studied through the use of pressure myography to determine vascular morphology, mechanics, and myogenic responsiveness, together with testing of constrictor and dilator function. Small arteries from patients with EH demonstrated eutrophic inward remodeling and an increased distensibility. Vessels from type 2D patients demonstrated hypertrophy, a further increase in distensibility, and a highly significant loss of myogenic responsiveness compared with patients with EH and control patients. Vasoconstrictor function to norepinephrine was normal in patients with type 2D and type 2DϩH and EH. Endothelium-dependent dilation was normal in patients with EH but abnormal in patients with type 2D and type 2DϩH. There was a significant correlation between dilator impairment and the degree of dyslipidemia recorded in all groups. Conclusions-These results demonstrate vascular hypertrophy in small arteries from patients with type 2D. This could be a consequence of impaired myogenic responsiveness, which will increase wall stress for a given intraluminal pressure, which may be a stimulus for vascular hypertrophy. A substantial proportion of endothelial dysfunction can be attributed to an effect of the abnormal lipid profile seen in such patients. (Circulation. 2002;106:3037-3043.)

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“…In the experimental setting, FFAs, especially oleic acid and linoleic acid, have been shown to impair EDV [32]. Also, small dense LDL, involved in the generation of oxidized LDL, could attenuate EDV possibly through oxygen free radical formation [33], whilst HDL cholesterol has been shown to improve EDV [34].…”

Section: Discussionmentioning

confidence: 99%

Effects of age, gender and metabolic factors on endothelium‐dependent vasodilation: a population‐based study

Sarabi

Millgård

Lind

1999

Journal of Internal Medicine

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Abstract. Sarabi M, Millga Êrd J, Lind L (University Hospital, Uppsala, Sweden). Effects of age, gender and metabolic factors on endothelium-dependent vasodilation: a population-based study. J Intern Med 1999; 246: 265±274.Objectives. A progressive decline in endotheliumdependent vasodilation (EDV) in the human forearm with age has previously been reported. The aim of this study was to evaluate the interplay between age, gender and metabolic factors on EDV in healthy subjects in a population-based study. Setting. Tertiary university hospital. Subjects and design. Thirty-six healthy men and 30 women, aged 20±69 years, underwent measurements of forearm blood flow (FBF) at rest and during local infusions of 2 and 4 mg min 21 of metacholine (evaluating EDV) and 5 and 10 mg min 21 of sodium nitroprusside (evaluating endothelium-independent vasodilation, EIDV) and during reactive hyperaemia by venous occlusion plethysmography. Results. Age was inversely related to EDV (r = ± 0.41, P , 0.05 in men; r = ± 0.61, P , 0.01 in women) and maximal FBF during reactive hyperaemia in both men and women. EIDV was significantly related to age in an inverse way in women only. EDV was more pronounced in females than in males before menopause (48 6 3 SD years, 635 6 186 vs. 502 6 269% in males, P , 0.05), but similar in women and men thereafter (374 6 141 vs. 370 6 185% in men). The slope of the regression line for the relationship between age and EDV was flatter in premenopausal than in postmenopausal women (± 2.3 vs. ± 6.4), whilst this slope was similar in younger and older men (± 5.5 vs. ± 5.3). In multiple regression analysis, fasting blood glucose levels and the waist/hip ratio remained the only significant predictors of EDV in men (P , 0.01 for both), whilst age was the only significant independent predictor of EDV in women (P , 0.01). Conclusion. The interplay between age and metabolic factors as determinants of endothelial function is different in healthy men and women.

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Inactivation of endothelial derived relaxing factor by oxidized lipoproteins.

Cited by 425 publications

References 41 publications

Influence of chronic treatment with a nitric oxide donor on fatty streak development and reactivity of the rabbit aorta

Influence of chronic treatment with a nitric oxide donor on fatty streak development and reactivity of the rabbit aorta

Vascular Structural and Functional Changes in Type 2 Diabetes Mellitus

Effects of age, gender and metabolic factors on endothelium‐dependent vasodilation: a population‐based study

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