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  • 1
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    Online Resource
    Consequences of Hyperhomocyst(e)inemia on Vascular Function in Atherosclerotic Monkeys
    Ovid Technologies (Wolters Kluwer Health) ; 1997
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 17, No. 11 ( 1997-11), p. 2930-2934
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 17, No. 11 ( 1997-11), p. 2930-2934
    Abstract: Abstract Moderate elevation of plasma homocyst(e)ine is associated with increased risk for atherosclerotic vascular disease. In a previous study, we observed impaired vascular function in nonatherosclerotic monkeys with moderate hyperhomocyst(e)inemia. In this study, we tested the hypothesis that dietary intervention to lower plasma homocyst(e)ine corrects vascular dysfunction in atherosclerotic monkeys. Cynomolgus monkeys were fed an atherogenic diet that produces both hypercholesterolemia and moderate hyperhomocyst(e)inemia. After 17 months, the atherogenic diet was supplemented with B vitamins (5 mg folic acid, 400 μg vitamin B-12, and 20 mg vitamin B-6 daily) for 6 months. Total plasma homocyst(e)ine decreased from 12.8±2.8 to 3.5±0.3 μmol/L (n=9; mean±SE; P 〈 .01) after vitamins were added to the diet, but plasma cholesterol remained elevated (522±63 versus 514±41 mg/dL; P 〉 .05). In response to intra-arterial infusion of collagen, blood flow to the leg decreased by 30±3% and 38±5%, respectively, before and after vitamin supplementation ( P 〉 .05). In vivo responses of resistance vessels to endothelium-dependent vasodilators (acetylcholine or ADP) were impaired at baseline and did not improve after vitamin supplementation. In carotid artery studied ex vivo, relaxation to low doses of acetylcholine improved after vitamin supplementation, but maximal relaxation remained impaired. Ex vivo thrombomodulin anticoagulant activity was threefold higher in monkeys fed the atherogenic diet (with or without B vitamins) than in normal monkeys ( P 〈 .05). We conclude that normalization of plasma homocyst(e)ine is insufficient to restore normal vascular function in atherosclerotic monkeys with persistent hypercholesterolemia and that atherosclerosis, with or without hyperhomocyst(e)inemia, is associated with elevated thrombomodulin activity.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.17.11.2930
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1997
    detail.hit.zdb_id: 1494427-3
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  • 2
    Online Resource
    Online Resource
    Folate dependence of hyperhomocysteinemia and vascular dysfunction in cystathionine β-synthase-deficient mice
    American Physiological Society ; 2000
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 279, No. 3 ( 2000-09-01), p. H970-H975
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 279, No. 3 ( 2000-09-01), p. H970-H975
    Abstract: Hyperhomocysteinemia is a risk factor for stroke, myocardial infarction, and venous thrombosis. Moderate hyperhomocysteinemia is associated with impaired endothelial function, but the mechanisms responsible for endothelial dysfunction in hyperhomocysteinemia are poorly understood. We have used genetic and dietary approaches to produce hyperhomocysteinemia in mice. Heterozygous cystathionine β-synthase-deficient mice (CBS +/−), which have a selective defect in homocysteine transsulfuration, and wild-type (CBS +/+) littermates were fed either a control diet or a diet that is relatively deficient in folic acid for 6 wk. Plasma total homocysteine was 5.3 ± 0.7 μM in CBS +/+ mice and 6.4 ± 0.6 μM in CBS +/− mice ( P = 0.3) given the control diet. Plasma total homocysteine was 11.6 ± 4.5 μM in CBS +/+ mice and 25.1 ± 3.2 μM in CBS +/− mice ( P = 0.004) given a low-folate diet. In mice fed the control diet, relaxation of aortic rings in response to the endothelium-dependent vasodilator acetylcholine did not differ significantly between CBS +/+ mice and CBS +/− mice. In contrast, in mice fed a low-folate diet, maximal relaxation to acetylcholine was markedly impaired in CBS +/− mice (58 ± 9%) compared with CBS +/+ mice (84 ± 4%) ( P = 0.01). No differences in relaxation to the endothelium-independent vasodilator sodium nitroprusside were observed among the four groups of mice. These data indicate that CBS-deficient mice are predisposed to hyperhomocysteinemia during dietary folate deficiency, and moderate hyperhomocysteinemia is associated with marked impairment of endothelial function in mice.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.2000.279.3.H970
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2000
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 3
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    Online Resource
    Impaired Anticoagulant Response to Infusion of Thrombin in Atherosclerotic Monkeys Associated With Acquired Defects in the Protein C System
    Ovid Technologies (Wolters Kluwer Health) ; 1999
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 19, No. 7 ( 1999-07), p. 1744-1750
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 19, No. 7 ( 1999-07), p. 1744-1750
    Abstract: Abstract —To examine the effects of atherosclerosis on the protein C anticoagulant pathway in vivo, we measured anticoagulant responses to intravenous administration of human α-thrombin or activated protein C (APC) in cynomolgus monkeys. Two groups of monkeys were fed either a control diet (n=18) or an atherogenic diet (n=12) that produces both hypercholesterolemia and moderate hyperhomocyst(e)inemia. A third group (n=8) was fed an atherogenic diet for 15 months, and then fed the atherogenic diet supplemented with B vitamins for 6 months to correct the hyperhomocyst(e)inemia. The plasma homocyst(e)ine level was higher in monkeys fed the atherogenic diet (9.6±1.0 μmol/L) than in monkeys fed the control diet (3.7±0.2 μmol/L) or the atherogenic diet with B vitamins (3.6±0.2 μmol/L) ( P 〈 0.001). Infusion of thrombin produced a much greater prolongation of the activated partial thromboplastin time in monkeys fed the control diet (52±10 seconds) than in monkeys fed the atherogenic diet either with (24±4 seconds) or without (27±5 seconds) supplemental B vitamins ( P 〈 0.02). Thrombin-dependent generation of circulating APC was higher in control (294±17 U/mL) than in atherosclerotic (240±14 U/mL) monkeys ( P 〈 0.05), although levels of fibrinogen, plasminogen, D-dimer, and thrombin-antithrombin complexes were similar in each group. Injection of human APC produced a similar prolongation of the activated partial thromboplastin time in control (31±3 seconds) and atherosclerotic (29±2 seconds) monkeys. These findings provide evidence for impaired anticoagulation, due partly to decreased formation of APC, in atherosclerosis. The blunted anticoagulant response to thrombin in hypercholesterolemic monkeys was not corrected by supplementation with B vitamins.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.19.7.1744
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1999
    detail.hit.zdb_id: 1494427-3
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  • 4
    Online Resource
    Online Resource
    Effect of hyperhomocysteinemia on protein C activation and activity
    American Society of Hematology ; 2002
    In:  Blood Vol. 100, No. 6 ( 2002-09-15), p. 2108-2112
    Details
    In: Blood, American Society of Hematology, Vol. 100, No. 6 ( 2002-09-15), p. 2108-2112
    Abstract: Hyperhomocysteinemia has been proposed to inhibit the protein C anticoagulant system through 2 mechanisms: decreased generation of activated protein C (APC) by thrombin, and resistance to APC caused by decreased inactivation of factor Va (FVa). We tested the hypotheses that generation of APC by thrombin is impaired in hyperhomocysteinemia in monkeys and that hyperhomocysteinemia produces resistance to APC in monkeys, mice, and humans. In a randomized crossover study, cynomolgus monkeys were fed either a control diet or a hyperhomocysteinemic diet for 4 weeks. Plasma total homocysteine (tHcy) was approximately 2-fold higher when monkeys were on the hyperhomocysteinemic diet than when they were on the control diet (9.8 ± 2.0 μM versus 5.6 ± 1.0 μM; P  〈  .05). After infusion of human thrombin (25 μg/kg of body weight), the peak level of plasma APC was 136 ± 16 U/mL in monkeys fed the control diet and 127 ± 13 U/mL in monkeys fed the hyperhomocysteinemic diet (P  〉  .05). The activated partial thromboplastin time was prolonged to a similar extent by infusion of thrombin in monkeys fed the control diet and in those fed the hyperhomocysteinemic diet. The sensitivity of plasma FV to human APC was identical in monkeys on control diet and those on hyperhomocysteinemic diet. We also did not detect resistance of plasma FV to APC in hyperhomocysteinemic mice deficient in cystathionine β-synthase (plasma tHcy, 93 ± 16 μM) or in human volunteers with acute hyperhomocysteinemia (plasma tHcy, 45 ± 6 μM). Our findings indicate that activation of protein C by thrombin and inactivation of plasma FVa by APC are not impaired during moderate hyperhomocysteinemia in vivo.
    Type of Medium: Online Resource
    ISSN: 1528-0020 , 0006-4971
    URL: Article
    DOI: 10.1182/blood-2002-03-0727
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2002
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
    Online Resource
    Online Resource
    Endothelial Dysfunction and Elevation of S -Adenosylhomocysteine in Cystathionine β-Synthase–Deficient Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2001
    In:  Circulation Research Vol. 88, No. 11 ( 2001-06-08), p. 1203-1209
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 88, No. 11 ( 2001-06-08), p. 1203-1209
    Abstract: Abstract —Hyperhomocysteinemia is associated with increased risk for cardiovascular events, but it is not certain whether it is a mediator of vascular dysfunction or a marker for another risk factor. Homocysteine levels are regulated by folate bioavailability and also by the methyl donor S -adenosylmethionine (SAM) and its metabolite S -adenosylhomocysteine (SAH). We tested the hypotheses that endothelial dysfunction occurs in hyperhomocysteinemic mice in the absence of folate deficiency and that levels of SAM and SAH are altered in mice with dysfunction. Heterozygous cystathionine β-synthase–deficient (CBS +/– ) and wild-type (CBS +/+ ) mice were fed a folate-replete, methionine-enriched diet. Plasma levels of total homocysteine were elevated in CBS +/– mice compared with CBS +/+ mice after 7 weeks (27.1±5.2 versus 8.8±1.1 μmol/L; P 〈 0.001) and 15 weeks (23.9±3.0 versus 13.0±2.3 μmol/L; P 〈 0.01). After 15 weeks, but not 7 weeks, relaxation of aortic rings to acetylcholine was selectively impaired by 35% ( P 〈 0.05) and thrombomodulin anticoagulant activity was decreased by 20% ( P 〈 0.05) in CBS +/– mice. Plasma levels of folate did not differ between groups. Levels of SAH were elevated ≈2-fold in liver and brain of CBS +/– mice, and correlations were observed between plasma total homocysteine and SAH in liver ( r =0.54; P 〈 0.001) and brain ( r =0.67; P 〈 0.001). These results indicate that endothelial dysfunction occurs in hyperhomocysteinemic mice even in the absence of folate deficiency. Endothelial dysfunction in CBS +/– mice was associated with increased tissue levels of SAH, which suggests that altered SAM-dependent methylation may contribute to vascular dysfunction in hyperhomocysteinemia.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/hh1101.092180
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2001
    detail.hit.zdb_id: 1467838-X
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  • 6
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    Supplementation of Atherogenic Diet With B Vitamins Does Not Prevent Atherosclerosis or Vascular Dysfunction in Monkeys
    Ovid Technologies (Wolters Kluwer Health) ; 2001
    In:  Circulation Vol. 103, No. 7 ( 2001-02-20), p. 1006-1011
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 103, No. 7 ( 2001-02-20), p. 1006-1011
    Abstract: Background —Hyperhomocysteinemia is associated with increased risk of atherosclerotic and thrombotic vascular disease. In many patients, hyperhomocysteinemia can be treated or prevented by dietary supplementation with B vitamins, but the clinical benefit of B vitamins for the prevention of vascular disease has not been proven. Methods and Results —Using an atherogenic diet that produces both hyperhomocysteinemia and hypercholesterolemia, we tested the hypothesis that dietary supplementation with B vitamins (folic acid, vitamin B 12 , and vitamin B 6 ) would prevent hyperhomocysteinemia, vascular dysfunction, and atherosclerotic lesions in monkeys. After 17 months, plasma total homocysteine increased from 3.6±0.3 to 11.8±1.7 μmol/L in monkeys fed an unsupplemented atherogenic diet ( P 〈 0.01) but did not increase in monkeys fed an atherogenic diet supplemented with B vitamins (3.8±0.3 μmol/L). Serum cholesterol increased from 122±7 to 550±59 mg/dL in the unsupplemented group ( P 〈 0.001) and from 118±5 to 492±55 mg/dL in the supplemented group ( P 〈 0.001). Responses to endothelium-dependent vasodilators, both in resistance vessels in vivo and in the carotid artery ex vivo, were impaired to a similar extent in groups that did and did not receive vitamin supplements. Anticoagulant responses to the infusion of thrombin were also impaired to a similar extent in both groups. Vitamin supplementation failed to prevent intimal thickening in the carotid or iliac arteries. Conclusions —These findings demonstrate that supplementation with B vitamins prevents hyperhomocysteinemia but is not sufficient to prevent the development of vascular dysfunction or atherosclerotic lesions in monkeys with marked hypercholesterolemia, even in the absence of preexisting atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/01.CIR.103.7.1006
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2001
    detail.hit.zdb_id: 1466401-X
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