Homocysteine accelerates endothelial cell senescence

Xu, Dong-Ling; Neville, Richard F.; Finkel, Toren

doi:10.1016/s0014-5793(00)01278-3

Cited by 194 publications

(128 citation statements)

References 21 publications

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“…These conditions induce premature cell senescence and alteration of cell function such as increased expression of plasminogen activator inhibitor type I (PAI-I), intracellular adhesion molecule I (ICAM-I), and fibronectin, which may contribute to the development of atherosclerosis (13,21). The idea is supported by the observations by Campisi that some gene products are expressed differentially in senescent endothelial cells and play pathogenic roles in atherosclerosis (22).…”

Section: Discussionmentioning

confidence: 96%

Telomere Shortening of Peripheral Blood Mononuclear Cells in Coronary Disease Patients with Metabolic Disorders.

et al. 2003

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Objective Telomere shortening is correlated with cell turnover and aging, but it has been recently suggested to occur not only by aging but by several biochemical fac- Results The results demonstrated that HCand/or DM patients with coronary diseases have significantly shorter telomere length than healthy controls (p=0.0014). Conclusion Telomere shortening may be involved in the mechanismsthat promote coronary diseases under some circumstances of metabolic disorders. (Internal Medicine 42: 150-153, 2003)

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Section: Discussionmentioning

confidence: 96%

Telomere Shortening of Peripheral Blood Mononuclear Cells in Coronary Disease Patients with Metabolic Disorders.

et al. 2003

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“…Of note, folic acid supplementation seems to prevent NTD in some susceptible embryos by blocking accumulation of homocysteine, a cellular oxidant [53,54,55]. Many drugs that cause neural tube, and other, defects, including thalidomide [56], phenytoin [56,57], environmental aryl hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin [58], and ionizing radiation [59] induce oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects

et al. 2003

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Aims/hypothesis. Maternal diabetes increases oxidative stress in embryos. Maternal diabetes also inhibits expression of embryonic genes, most notably, Pax-3, which is required for neural tube closure. Here we tested the hypothesis that oxidative stress inhibits expression of Pax-3, thereby providing a molecular basis for neural tube defects induced by diabetic pregnancy. Methods. Maternal diabetes-induced oxidative stress was blocked with α-tocopherol (vitamin E), and oxidative stress was induced with the complex III electron transport inhibitor, antimycin A, using pregnant diabetic or non-diabetic mice, primary cultures of neurulating mouse embryo tissues, or differentiating P19 embryonal carcinoma cells. Pax-3 expression was assayed by quantitative RT-PCR, and neural tube defects were scored by visual inspection. Oxidation-induced DNA fragmentation in P19 cells was assayed by electrophoretic analysis.Results. Maternal diabetes inhibited Pax-3 expression and increased neural tube defects, and α-tocopherol blocked these effects. In addition, induction of oxidative stress with antimycin A inhibited Pax-3 expression and increased neural tube defects. In cultured embryo tissues, high glucose-inhibited Pax-3 expression, and this effect was blocked by α-tocopherol and GSHethyl ester, and Pax-3 expression was inhibited by culture with antimycin A. In differentiating P19 cells, antimycin A inhibited Pax-3 induction but did not induce DNA strand breaks. Conclusion/interpretation. Oxidative stress inhibits expression of Pax-3, a gene that is essential for neural tube closure. Impaired expression of essential developmental control genes could be the central mechanism by which neural tube defects occur during diabetic pregnancy, as well as other sources of oxidative stress. [Diabetologia (2003) 46:538-545]

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“…Changes in the intracellular redox potential could thus modulate specific cellular functions of vascular cells (Blache et al, 1999;Flohé et al, 1997;Lander, 1997;Sen and Packer, 1996). Interestingly, exposure of endothelial cells to homocysteine would accelerate the rate of cellular senescence and increase the amount of telomere length lost per population doubling, through a redox-dependent pathway (Xu et al, 2000). Additionally, the degree of endothelial senescence positively correlated with the level of expression of two surface molecules linked to vascular disease, the intracellular adhesion molecule-1 and type 1 plasminogen activation inhibitor (Xu et al, 2000).…”

Section: Durand Et Almentioning

confidence: 99%

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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Homocysteine accelerates endothelial cell senescence

Cited by 194 publications

References 21 publications

Telomere Shortening of Peripheral Blood Mononuclear Cells in Coronary Disease Patients with Metabolic Disorders.

Telomere Shortening of Peripheral Blood Mononuclear Cells in Coronary Disease Patients with Metabolic Disorders.

Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects

Impaired Homocysteine Metabolism and Atherothrombotic Disease

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