Human arterial endothelial cell detachment in vitro: its promotion by homocysteine and cysteine

Dudman, Nicholas P.B.; Hicks, Christine; Wang, J.; Wilcken, D. E. L.

doi:10.1016/0021-9150(91)90189-a

Cited by 106 publications

(46 citation statements)

References 21 publications

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“…Because cellular damage of endothelial cells exposed to homocysteine may be prevented by pretreatment of cells with catalase, which allows the detoxification of hydrogen peroxide that freely crosses the cell membrane (Starkebaum and Harlan, 1986;Wall et al, 1980), an increased oxidant stress may be a main mechanism of homocysteineinduced endothelial cell injury. Although cytotoxicity was not specific to homocysteine, endothelial cell detachment is also observed with cysteine (Dudman et al, 1991), an increase in the hydrogen peroxidesensitive cellular fluorescent probe, 2',7'-dichlorofluorescein, was observed in cultured endothelial cells exposed to homocysteine (Toborek and Hennig, 1996). Besides the initiation of lipid peroxidation at the cell surface, homocysteine auto-oxidation with trace metal ions, generating reactive oxygen species such as superoxide anion, hydrogen peroxide, hydroxyl, and thiol free radicals (Munday, 1989;Schöneich et al, 1989), would directly oxidize low-density lipoprotein (LDL) (Heinecke et al, 1987;Hirano et al, 1994;Wood and Graham, 1995).…”

Section: Hyperhomocysteinemia-mediated Oxidant Stress Through Imbalanmentioning

confidence: 86%

“…The reported reduced platelet survival has not been confirmed by others in homocystinuric patients, and in vitro results of platelet function abnormalities have been controversial (reviewed in Malinow, 1994;Stamler and Slivka, 1996). However, favoring the theory of hyperhomocysteinemia-induced platelet activation, in vitro studies have proposed that, besides its direct cytotoxicity that damages endothelial cells (Dudman et al, 1991;Starkebaum and Harlan, 1986;Wall et al, 1980), homocysteine alters endothelium antithrombotic properties (Harpel et al, 1996). Although data concerning the prostacyclin (PGI 2 ) biosynthesis by endothelial cells incubated with homocysteine are controversial (Graeber et al, 1982;Panganamala et al, 1986;Wang et al, 1993), homocysteine could impair the ability of these cells to inhibit platelet aggregation, probably by reducing nitric oxide (NO) bioavailability .…”

Section: Alterations Of Vascular Thromboresistancementioning

confidence: 99%

“…They also suggest that the elevation of homocysteine may have multifactorial effects, interacting with both the vascular wall structure and the blood coagulation system, with different outcomes depending on the tissue and on the consequent degree of hyperhomocysteinemia. Although additional studies are required to clarify the molecular mechanisms responsible for hyperhomocysteinemiainduced vascular disorders, there is evidence that the direct cytotoxicity of markedly elevated homocysteine and/or of its oxidized by-products (homocysteine thiolactone, homocysteine sulfinic acid, and homocysteic acid) damages endothelial cells (Dudman et al, 1991;Starkebaum and Harlan, 1986;Wall et al, 1980). This direct cytotoxicity may also cause alteration in the tertiary structure of proteins in connective tissue and hence affect the vascular wall structure (Lubec et al, 1996a;McCully, 1996;Rolland et al, 1995).…”

Section: Durand Et Almentioning

confidence: 99%

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Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

232

147

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SUMMARY:Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N 5,10 -methylenetetrahydrofolate reductase, and vitamin B 6 deficiency, perhaps associated with cystathionine ␤-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease. (Lab Invest 2001, 81:645-672).C ardiovascular diseases remain the leading cause of mortality in Western populations. Hyperlipoproteinemia, hypertension, diabetes, obesity, and tobacco smoking are the main risk factors for atherosclerosis and its thrombotic complications. However, these factors alone cannot account for all of the deaths caused by vascular pathologies.As early as 1969, clinical studies conducted in homocystinuric children revealed the importance of severe hyperhomocysteinemia in premature development of atherosclerosis and thromboembolism (McCully, 1983). According to numerous retrospective case-controlled studies, moderate increases in plasma homocysteine, which can be precisely quantitated by high performance liquid chromatography (HPLC), raise the risk for cardiovascular disease 2-fold, after adjusting for classic risk factors. Moreover, up to 20% to 40% of patients with vascular pathologies present moderate to intermediate hyperhomocysteinemia. However, results from prospective studies are inconsistent. Additionally, molecular mechanisms underlying hyperhomocysteinemia-induced vascular diseas...

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Section: Hyperhomocysteinemia-mediated Oxidant Stress Through Imbalanmentioning

confidence: 86%

Section: Alterations Of Vascular Thromboresistancementioning

confidence: 99%

Section: Durand Et Almentioning

confidence: 99%

See 1 more Smart Citation

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

232

147

View full text Add to dashboard Cite

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“…5 Endothelial injury appears to be an early event in the promotion of atherogenesis 6 and may be one mechanism whereby homocysteine leads to an increased risk of both arterial and venous disease. Studies in vitro have demonstrated that homocysteine may injure endothelium, 7,8 but the mechanism for such an effect is not yet known. Dietary modification to increase homocysteine levels in monkeys, including augmenting methionine intake, impairs vascular function.…”

mentioning

confidence: 99%

Hyperhomocysteinemia After an Oral Methionine Load Acutely Impairs Endothelial Function in Healthy Adults

et al. 1998

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Background-Elevated plasma homocysteine is a risk factor for arteriosclerosis, but a cause-and-effect relationship remains to be fully established. Endothelial dysfunction, an early event in the atherogenic process, has been shown to be associated with hyperhomocysteinemia in experimental and human studies. To further establish a direct relationship between changes in plasma homocysteine and endothelial dysfunction, we investigated whether moderate hyperhomocysteinemia induced by an oral methionine load would acutely impair flow-mediated endothelium-dependent vasodilatation in healthy adults. Methods and Results-Twenty-four healthy volunteers completed a randomized crossover study in which an oral methionine load (0.1 g/kg) was administered on 1 of 2 study days, 7 days apart. At each visit, plasma homocysteine and brachial artery endothelium-dependent and -independent dilatation were measured at baseline and at 4 hours. To further elucidate the temporal relationship between methionine, homocysteine, and endothelial function, an oral methionine load was administered in 10 subjects on a separate visit, and the time courses of plasma methionine, homocysteine, and flow-mediated brachial artery dilatation were measured at baseline and after 1, 2, 3, 4, and 8 hours.

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“…8 Although the exact mechanism of atherothrombosis associated with hyperhomocystinemia is not clearly understood, several studies have pointed to an association with inhibition of thrombomodulin activity, 9 reduction of protein C activation, 10,11 increased platelet aggregation, 12 and predisposition to endothelial cell injury. 13,14 Most of these studies, however, were in vitro studies, where supraphysiological concentrations of homocysteine were used.…”

mentioning

confidence: 99%

Relationships Between Homocysteine, Factor VIIa, and Thrombin Generation in Acute Coronary Syndromes

et al. 2000

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Background-It has been suggested by clinical, epidemiological, and experimental in vitro studies that homocysteine potentiates thrombin generation. This prothrombotic effect however has not previously been demonstrated in patients presenting with acute coronary syndromes (ACS). Methods and Results-Patients with ACS (n ϭ117) presenting with confirmed acute myocardial infarction (MI) (n ϭ57) or unstable angina pectoris (UAP) (n ϭ60) were consecutively recruited together with patients (n ϭ18) in whom the presenting chest pain was not of cardiac origin (NCP), included as controls. Plasma samples were collected on admission and before clinical intervention. Homocysteine was assayed by high performance liquid chromatography, and both Factor VIIa and prothrombin fragment F1ϩ2 were analyzed by ELISA. There were significant elevations in F1ϩ2 in MI (PϽ0.001) and UAP (Pϭ0.003), and modest elevations in Factor VIIa in UAP (PϽ0.05) compared with NCP but no differences in homocysteine levels among those groups. On dividing patients with ACS into quartiles of homocysteine, there was a stepwise increase in F1ϩ2 (PϽ0.0001) and of Factor VIIa (PϽ0.05). There were significant correlations in ACS between homocysteine and F1ϩ2 (rϭ0.46, PϽ0.0001), homocysteine and Factor VIIa (rϭ0.24, PϽ0.01), and F1ϩ2 and Factor VIIa (rϭ0.41, PϽ0.0001). There was no correlation between homocysteine and either F1ϩ2 (rϭϪ0.15, Pϭ0.57) or Factor VIIa (rϭ0.22, Pϭ0.37) in the NCP patients. Conclusions-Elevated plasma homocysteine is associated with and may cause elevated Factor VIIa and thrombin generation in patients presenting with ACS. These findings suggest an explanation for the prothrombotic effect of homocysteine in ACS.

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Human arterial endothelial cell detachment in vitro: its promotion by homocysteine and cysteine

Cited by 106 publications

References 21 publications

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Hyperhomocysteinemia After an Oral Methionine Load Acutely Impairs Endothelial Function in Healthy Adults

Relationships Between Homocysteine, Factor VIIa, and Thrombin Generation in Acute Coronary Syndromes

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