Homocysteine and endothelial vascular function

Hanratty, Colm G.; McAuley, Daniel F.; McGurk, C.; Johnston, G D

doi:10.1016/s0140-6736(05)79355-7

Cited by 30 publications

(17 citation statements)

References 4 publications

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“…One preliminary report in a limited number of subjects suggested that methionine loading did not alter forearm vasodilatation to acetylcholine. 18 We demonstrated in a substantial number of subjects that methionine loading does impair endothelium-dependent vasodilatation in resistance vessels, albeit partially. Importantly, endothelial dysfunction caused by experimental hyperhomocyst(e)inemia was completely prevented by administration of an antioxidant, ascorbic acid.…”

Section: Discussionmentioning

confidence: 75%

Role of Oxidant Stress in Endothelial Dysfunction Produced by Experimental Hyperhomocyst(e)inemia in Humans

et al. 1999

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Background-Moderate elevations in plasma homocyst(e)ine concentrations are associated with atherosclerosis and hypertension. We tested the hypothesis that experimental perturbation of homocysteine levels produces resistance and conduit vessel endothelial dysfunction and that this occurs through increased oxidant stress. Methods and Results-Oral administration of L-methionine (100 mg/kg) was used to induce moderate hyperhomocyst(e)inemia (Ϸ25 mol/L) in healthy human subjects. Endothelial function of forearm resistance vessels was assessed by use of forearm vasodilatation to brachial artery administration of the endothelium-dependent dilator acetylcholine. Conduit vessel endothelial function was assessed with flow-mediated dilatation of the brachial artery. Forearm resistance vessel dilatation to acetylcholine was significantly impaired 7 hours after methionine (methionine, 477Ϯ82%; placebo, 673Ϯ110%; Pϭ0.016). Methionine did not alter vasodilatation to nitroprusside and verapamil. Flow-mediated dilatation was significantly impaired 8 hours after methionine loading (0.3Ϯ2.7%) compared with placebo (8.2Ϯ1.6%, Pϭ0.01). Oral administration of the antioxidant ascorbic acid (2 g) prevented methionine-induced endothelial dysfunction in both conduit and resistance vessels (Pϭ0.03). Conclusions-Experimentally increasing plasma homocyst(e)ine concentrations by methionine loading rapidly impairs both conduit and resistance vessel endothelial function in healthy humans. Endothelial dysfunction in conduit and resistance vessels may underlie the reported associations between homocysteine and atherosclerosis and hypertension.Increased oxidant stress appears to play a pathophysiological role in the deleterious endothelial effects of homocysteine.

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Section: Discussionmentioning

confidence: 75%

Role of Oxidant Stress in Endothelial Dysfunction Produced by Experimental Hyperhomocyst(e)inemia in Humans

et al. 1999

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“…Whereas many reports described an altered peripheral vascular reactivity, 20 -24 other investigators did not find any differences in the functional integrity of peripheral vessels. [25][26][27] In an investigation of the CA mechanism in young healthy volunteers, no differences were reported. 28 In the present investigation, we found the NC mechanism to be unaffected by the same methionine challenge, as concluded from evaluation of Doppler data.…”

Section: Discussionmentioning

confidence: 99%

“…16 -19 Several studies in healthy young volunteers undergoing an oral methionine loading of 0.1 g/kg body weight demonstrated an impaired peripheral vascular reactivity. 20 -24 However, some reports found neither an altered peripheral vascular reactivity 25,26 nor a change in arterial rigidity under the same homocysteine challenge. 27 Similarly, for the cerebral autoregulation (CA) mechanism that maintains constant cerebral perfusion despite changes in arterial blood pressure, it was demonstrated that vascular reactivity was affected only in aged but not in young healthy subjects.…”

mentioning

confidence: 99%

Effects of Acute Hyperhomocysteinemia on the Neurovascular Coupling Mechanism in Healthy Young Adults

Rosengarten

Osthaus

Auch

et al. 2003

Stroke

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Background and Purpose-Hyperhomocysteinemia is a vascular risk factor that infers with the nitric oxide signaling pathway of endothelial vasoregulation. Most investigations in young healthy humans on the peripheral vasculature using a standardized methionine challenge demonstrated altered vascular reactivity. In contrast, the cerebral autoregulation mechanism was shown to be unaffected by the same methionine load. To obtain additional insight into the compensatory range of the cerebral vasculature during a methionine challenge, we tested the neurovascular coupling mechanism that adjusts cerebral blood flow in accordance with cortical activity. Methods-Fifteen healthy young adults (age, 24.7Ϯ2.3 years; 7 men) were tested with a functional transcranial Doppler test before and 3, 8, and 24 hours after administration of placebo, 20 mg folic acid, 20 mg folic acid and 0.1 g/kg body weight L-methionine, or L-methionine alone. Evoked blood flow response was evaluated according to a control system approach. Plasma concentrations of homocysteine, resting blood flow velocities, and control system parameters of flow velocity change were compared for each time point using a multiple analysis of variance test. Results-Homocysteine levels increased significantly compared with baseline (before, 7.6Ϯ1.9 mol/L; 3 hours, 22 Key Words: endothelium Ⅲ homocyst(e)ine Ⅲ ultrasonography, Doppler Ⅲ vasodilation T he neurovascular coupling (NC) mechanism adjusts local cerebral blood flow in accordance with the underlying cortical activity. [1][2][3][4] Whereas the detailed mechanisms remain to be resolved, there is good evidence that the biological elements of the NC mechanism functionally resemble a complex and cascaded control system. 1,2,4 -8 The vascular endothelium and its nitric oxide system play a crucial role in the NC-related vasoregulation. 4,9 -13 Hyperhomocysteinemia is an emerging vascular risk factor leading to endothelial dysfunction, atherosclerosis, and consequently parenchymal ischemia. 10 -13 The term "endothelial dysfunction" is assumed to describe in general a functional alteration of the vasculature, depending on some vasoregulative mechanism. 14,15 Under acute hyperhomocysteinemia, it is hypothesized to be caused by a decrease in availability of nitric oxide. 16 -19 Several studies in healthy young volunteers undergoing an oral methionine loading of 0.1 g/kg body weight demonstrated an impaired peripheral vascular reactivity. 20 -24 However, some reports found neither an altered peripheral vascular reactivity 25,26 nor a change in arterial rigidity under the same homocysteine challenge. 27 Similarly, for the cerebral autoregulation (CA) mechanism that maintains constant cerebral perfusion despite changes in arterial blood pressure, it was demonstrated that vascular reactivity was affected only in aged but not in young healthy subjects. 28 An attenuation of the endothelium-dependent cerebrovascular reactivity was found consistently only in animal experiments using high concentrations of homocysteine (1 mmol/L)...

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“…2). As endothelial dysfunction is a commonly observed pathology in mild hyperhomocyst(e)inemia in humans, either with acute elevation of tHcy levels after a methionine challenge (9)(10)(11)(12) or chronic hyperhomocyst(e)inemic states (13, Fig. 3.…”

Section: Discussionmentioning

confidence: 99%

“…Animal models of mild hyperhomocyst(e)inemia manifest impaired endothelium-dependent vasoreactivity and regulation of blood flow, whether induced by vitamin deficiency (6), disruption of the cystathionine ␤-synthase (CBS) gene (7), or both (8). Impaired endothelium-dependent vasodilator function, but preserved endothelium-independent vasodilator response, is also a common finding in humans with either acutely elevated plasma tHcy levels after a methionine challenge (9)(10)(11)(12) or with chronic, mild hyperhomocyst(e)inemia (13,14). In accordance with these in vivo findings, homocysteine (HcyH) has been shown to decrease the production and͞or bioactivity of NO and Snitrosothiols by cultured endothelial cells (15,16).…”

mentioning

confidence: 99%

Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction

Weiss

Heydrick

Bierl

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

197

140

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Homocyst(e)ine (Hcy) inhibits the expression of the antioxidant enzyme cellular glutathione peroxidase (GPx-1) in vitro and in vivo, which can lead to an increase in reactive oxygen species that inactivate NO and promote endothelial dysfunction. In this study, we tested the hypothesis that overexpression of GPx-1 can restore the normal endothelial phenotype in hyperhomocyst(e)inemic states. Heterozygous cystathionine ␤-synthase-deficient (CBS (؊/؉) ) mice and their wild-type littermates (CBS (؉/؉) ) were crossbred with mice that overexpress GPx-1 [GPx-1 (tg؉) mice]. GPx-1 activity was 28% lower in CBS (؊/؉) ͞GPx-1 (tg؊) compared with CBS (؉/؉) ͞GPx-1 (tg؊) mice (P < 0.05), and CBS (؊/؉) and CBS (؉/؉) mice overexpressing GPx-1 had 1.5-fold higher GPx-1 activity compared with GPx-1 nontransgenic mice (P < 0.05). Mesenteric arterioles of CBS (؊/؉) ͞ GPx-1 (tg؊) mice showed vasoconstriction to superfusion with ␤-methacholine and bradykinin (P < 0.001 vs. all other groups), whereas nonhyperhomocyst(e)inemic mice [CBS (؉/؉) ͞GPx-1 (tg؊) and CBS (؉/؉) ͞GPx-1 Mild hyperhomocyst(e)inemia is a risk factor for atherothrombotic vascular disease (reviewed in refs. 1-5). Endothelial dysfunction appears to play a key role in homocyst(e)ine (Hcy)-mediated vascular pathophysiology. Animal models of mild hyperhomocyst(e)inemia manifest impaired endothelium-dependent vasoreactivity and regulation of blood flow, whether induced by vitamin deficiency (6), disruption of the cystathionine ␤-synthase (CBS) gene (7), or both (8). Impaired endothelium-dependent vasodilator function, but preserved endothelium-independent vasodilator response, is also a common finding in humans with either acutely elevated plasma tHcy levels after a methionine challenge (9-12) or with chronic, mild hyperhomocyst(e)inemia (13,14). In accordance with these in vivo findings, homocysteine (HcyH) has been shown to decrease the production and͞or bioactivity of NO and Snitrosothiols by cultured endothelial cells (15,16).One mechanism proposed to explain the adverse effects of Hcy on endothelial function involves oxidant stress with resulting depletion of bioavailable NO (17). HcyH undergoes autooxidation when added to plasma, leading to the formation of reactive oxygen species, including hydrogen peroxide and superoxide anion (18). Superoxide anion can react with NO to form peroxynitrite, which leads to inactivation of its biological function (19). Hydrogen peroxide decomposes to the toxic oxygen species hydroxyl radical, which is highly reactive and causes lipid peroxidation. Elevated levels of lipid peroxides lead to an increase in peroxyl radicals that can, as well, inactivate NO through the formation of lipid peroxynitrites. Homocysteineinduced vascular oxidant stress may be additionally aggravated by an Hcy-mediated, specific decrease in the expression of the cellular isoform of glutathione peroxidase (GPx-1), as recently shown in vitro and in vivo (15, 20, §). This key enzyme for the cellular defense against oxidant stress uses glutathione to reduce hydro...

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Homocysteine and endothelial vascular function

Cited by 30 publications

References 4 publications

Role of Oxidant Stress in Endothelial Dysfunction Produced by Experimental Hyperhomocyst(e)inemia in Humans

Role of Oxidant Stress in Endothelial Dysfunction Produced by Experimental Hyperhomocyst(e)inemia in Humans

Effects of Acute Hyperhomocysteinemia on the Neurovascular Coupling Mechanism in Healthy Young Adults

Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction

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