STEVEN LENTZ

..Thrombomodulin anticoagulant activity in aorta decreased by 34 +/- 15% in hyperhomocyst(e)inemic monkeys (P = 0.03). We conclude that diet-induced moderate hyperhomocyst(e)inemia is associated with altered vascular function...

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..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...

..We tested the hypothesis that anticoagulant responses to thrombin increase toward normal during regression of atherosclerosis...

..Until we know the results of ongoing clinical trials of homocysteine-lowering therapy, testing for and treating elevated homocysteine is probably justified only in patients with known cardiovascular disease or who are at high risk...

..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...

..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...

..The blunted anticoagulant response to thrombin in hypercholesterolemic monkeys was not corrected by supplementation with B vitamins...

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..Additional studies are required to determine the mechanisms by which ADMA accumulates in hyperhomocysteinemia and to define the importance of ADMA in the endothelial dysfunction of hyperhomocysteinemia in vivo...

..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...

..Mechanical ventilation with maintenance of normal blood gases may enhance the physiological insight gained from experimental models of carotid artery thrombosis in mice...

..These data provide one potential mechanism for the fetal hemorrhage observed in SLP-76-deficient mice and reveal that SLP-76 expression is required for optimal receptor-mediated signal transduction in platelets as well as T lymphocytes...

..Severe deficiency of thrombomodulin anticoagulant activity does not appear to alter reepithelialization but may influence collagen production by fibroblasts in the wound matrix...

..We tested the hypothesis that deficiency of cellular glutathione peroxidase (GPx-1) enhances susceptibility to endothelial dysfunction in mice with moderate hyperhomocysteinemia...

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..The recent development of transgenic mice with altered ADMA metabolism should provide further mechanistic insights into the role of ADMA in hyperhomocysteinemia...

..05) by simultaneous incubation with DEANO or tiron. Thus, acute HHcy increases arterial permeability by generating O2- to an extent whereby nitric oxide bioavailability is reduced...

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..The amount of complex APC:PCI is detected with an anti-human PCI monoclonal antibody. The assay shows improved sensitivity versus enzyme immunocapture assays commonly used to detect human APC and considerably reduces the processing time...

..We tested the hypothesis that hyperhomocysteinemia and hypercholesterolemia promote arterial thrombosis in mice...

..The link between homocysteine, PPMT, PP2A methylation, and key CNS proteins involved in AD pathogenesis provides new mechanistic insights into this disorder...

..We tested the hypothesis that vasomotor function is impaired in cerebral arterioles during hypercholesterolemia through a mechanism that involves oxidative stress...

..Our data suggest that testosterone-dependent regulation of human CBS in kidney may contribute to sex-dependent differences in homocysteine transsulfuration...

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..05), and lower Delta6-desaturase activity (p<0.001) in liver from mice with HHcy. These findings suggest that methylation silencing of liver Fads2 expression and changes in liver fatty acids may contribute to the pathology of HHcy...

..ADMA is hydrolyzed by dimethylarginine dimethylaminohydrolases (DDAHs). The goal of this study was to determine whether overexpression of human DDAH-1 in transgenic (DDAH-1-Tg) mice inhibits the vascular effects of ADMA...

..Thus, genetic and pharmacological evidence suggests a major role for glutathione peroxidase-1 and hydrogen peroxide in Ang II-induced effects on vascular function...

..We also summarize the major vascular phenotypes observed in these murine models...

..Our findings demonstrate that hyperhomocysteinemia causes tissue-specific decreases in DDAH expression without altering plasma ADMA levels in mice with endothelial dysfunction...

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..These findings suggest that hyperhomocysteinemia promotes cerebral vascular hypertrophy and altered cerebral vascular mechanics, both of which may contribute to the increased incidence of stroke associated with hyperhomocysteinemia...

..Thus, both GPVI-dependent and GPVI-independent pathways contribute to collagen-induced platelet procoagulant activity...

..CONCLUSIONS: Superoxide is a key mediator of endothelial dysfunction in the cerebral circulation during diet-induced hyperhomocysteinemia...

..These findings suggest that PF4 may play a previously unsuspected physiologic role in enhancing APC generation...

..CONCLUSIONS: Multiple cellular stress pathways, including ER stress, are associated with atherosclerotic lesion development in apoE-/- mice...

..The prevalence of other thrombosis-associated alleles did not differ between TM patients and control subjects. These findings suggest that factor V Leiden may be a pathogenic risk factor in TM patients that have normal VWCP activity...

..05, r = 0.620). We conclude that hyperhomocysteinemia produces tissue-specific changes in H19 DMD methylation and increased vascular expression of H19 in adult mice...

..We tested the hypothesis that deficiency of MS impairs endothelial function in mice heterozygous for disruption of the Mtr gene, which encodes MS...

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..These findings demonstrate that the Mthfr(+/-) genotype sensitizes mice to diet-induced hyperhomocysteinemia and that hyperhomocysteinemia alters tissue methylation capacity and impairs endothelial function in cerebral microvessels...

..Additionally, depletion of platelets in normal mice results in decreased antigen-specific antibody production...

..These results implicate CypD and the MPTP as critical regulators of platelet activation and suggest a novel CypD-dependent negative-feedback mechanism regulating arterial thrombosis...

..We evaluated whether changes in plasma levels of OxPL associated with apolipoprotein B-100 (apoB-100) reflect changes in OxPL content in atherosclerotic plaques during dietary-induced atherosclerosis progression and regression...

..We conclude that FcRgamma, but not factor XIIIA, is essential for formation of highly procoagulant coated platelets following dual stimulation with collagen and thrombin...

..The goals of this project are to define the molecular mechanisms by which hyperhomocysteinemia and hypercholesterolemia, alone or in combination, lead to adverse vascular events, and to identify new targets for therapy. ..

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..This project has the potential to suggest novel therapeutic approaches to the prevention and treatment of vascular disease associated with hyperhomocysteinemia. ..

..Aim 2, will test the hypothesis that vascular dysfunction in hyperhomocysteinemic mice is caused by increased oxidative stress in vivo. Aim 3 will attempt to determine the mechanisms of elevation of ADMA in hyperhomocysteinemia. ..

..The goals of this project are to define the molecular mechanisms by which hyperhomocysteinemia and hypercholesterolemia, alone or in combination, lead to adverse vascular events, and to identify new targets for therapy. ..