同型半胱氨酸与动脉粥样硬化

高同型半胱氨酸血症 (HH)是引起动脉粥样硬化的危险因素 ,可通过增加机体氧化应激因子的细胞毒性作用 ,损害内皮细胞而引起动脉粥样硬化。某些营养素可以防治HH引起的动脉样硬化症状。     

Homocysteine and atherosclerosis.

Elevated plasma total homocysteine is an independent risk factor for atherosclerotic vascular disease. Risk rises continuously across the spectrum of homocysteine concentrations and may become appreciable at levels greater than 10 mumol/l. A compelling case can be made for screening all individuals with atherosclerotic disease or at high risk. A reasonable, but unproven, goal for treatment is a plasma total homocysteine concentration less than 10 mumol/l. Folic acid is the mainstay of treatment, but vitamins B12 and B6 may have added benefit in selected patients. The results of ongoing randomized placebo-controlled trials will not be available for several years, but will help determine whether homocysteine lowering reduces the risk of cardiovascular disease.     

同型半胱氨酸与阿尔采末病

阿尔采末病 (AD)是多因素共同作用的危害公众健康的复杂疾病 ,是神经科学工作者关注的焦点。近年来 ,有报道显示 ,血浆中同型半胱氨酸 (Hcy)的浓度与AD有密切联系。本文就血浆中Hcy的浓度与AD发生、发展的联系、可能的作用机制 ,以及两者联系的应用前景作一简述     

Homocysteine and oxidative stress

Summary. Hyperhomocysteinemia is an independent risk factor for cardiovascular disease (ischemic disease, such as stroke and myocardial infarction, and arterial and venous thrombotic events) in the general population. We can assume that the association is causal, based on the example of homocystinuria, and on the evidence put forward by several basic science and epidemiological studies; however, the results of large intervention trials, which will grant further support to this hypothesis, are not yet available. In addition, the mechanisms underlying this relationship, and also explaining the several toxic effects of homocysteine, related or not to cardiovascular disease, are unclear. Oxidation is one of the most favored postulated mechanisms; others are nitrosylation, acylation, and hypomethylation. Regarding the relative importance of these mechanisms, each of these hold pros and cons, and these are weighed in order to propose a balance of evidence.     

同型半胱氨酸与冠心病

随着社会的进步以及人类生活水平的提高,冠心痛的发病率也逐年提高,目前已经成为全球死亡率最高的疾病之一,同时医学水平的不断发展也使得人们对冠心病有了更进一步的研究.近年来同型半胱氨酸越来越受到人们的关注,众多研究表明,高同型半胱氨酸血症是冠心痛的独立危险因子,可以影响冠心病的严重程度及预后.但是迄今为止,同型半胱氨酸在冠心病发病中的确切机制尚不完全明确,认为主要与血管内皮损伤、血管平滑肌细胞增殖凋亡、破坏凝血纤溶系统、影响糖、蛋白质、脂质代谢等方面有关.针对高同型半胱氨酸血症的治疗,对于改善冠心病患者的预后有一定疗效.因此,本文就同型半胱氨酸冠心痛的关系作一综述,从而为临床更好的防治冠心痛提供相关的资料.     

Homocysteine accelerates endothelial cell senescence

In this study we demonstrate that exposure of cultured endothelial cells to homocysteine significantly accelerates the rate of endothelial senescence. Examination of telomere length demonstrates that homocysteine increases the amount of telomere length lost per population doubling. The effects of homocysteine on both senescence and telomere length are inhibited by treatment with the peroxide scavenger catalase. Chronic exposure of endothelial cells to homocysteine also increases the expression of two surface molecules linked to vascular disease, intracellular adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1). Interestingly, the level of expression of both ICAM-1 and PAI-1 correlates with the degree of endothelial senescence. Taken together, these results suggest that homocysteine accelerates the rate of cellular senescence through a redox-dependent pathway. In addition, it suggests that chronic oxidative stress in the vessel wall may hasten the rate of senescence and that the senescent endothelial cell may in turn be pro-atherogenic.     

Homocysteine levels in acromegaly patients

Acromegaly is associated with a two to three-fold increase in mortality related predominantly to cardiovascular disease. The excess mortality is associated most closely with higher levels of growth hormone (GH). Survival in acromegaly may be normalized to a control age-matched rate by controlling GH levels; in particular, GH levels less than 2.5 ng/mL are associated with survival rates equal to those of the general population. Hyperhomocysteinemia has also been recognized as a risk factor for cardiovascular disease, yet there are limited data on the prevalence of hyperhomocysteinemia in patients with acromegaly. Eighteen acromegaly patients (7 male, 11 female, mean age 42.8 +/- 11.0 years) in our endocrine clinic consented to having the following tests performed: complete blood count (CBC), thyroid hormones, folic acid, vitamin B12, plasma homocysteine levels, uric acid, fibrinogen, CRP, fasting glucose, insulin, C-peptide, total serum cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, GH, insulin-like growth factor-1 (IGF-1) and GH levels after an oral glucose tolerance test (OGTT). By history, fourteen had macroadenomas and four had microadenomas; eight had hypertension; two had glucose intolerance, and four had diabetes. Fifteen had had transsphenoidal or transfrontal surgery: two had been cured, but 13 others were taking long-acting octreotide. Five patients had undergone radiotherapy and the acromegaly in two was treated primarily with long-acting octreotide. CBC, thyroid hormone, folic acid, and vit B12 levels were normal in all patients. We divided the patients into two groups according to mean GH levels after an OGTT: Group 1 (GH<2.5 ng/mL, n=10), and Group 2 (GH<2.5 ng/mL, n=8). Comparison of the two groups using Mann-Whitney U testing revealed statistically significant lower levels in Group 1 of the following parameters: GH (1.91 +/- 0.90 vs. 8.58 +/- 5.55 ng/mL, p=0.002), IGF-1 (338.30 +/- 217.90 vs. 509.60 +/- 293.58 ng/dL, p=0.06), GH after an OGTT (1.42 +/- 0.81 vs. 9.01 +/- 4.53 ng/mL, p=0.001), plasma homocysteine (12.85 +/- 4.47 vs. 18.20 +/- 4.99 micromol/L, p=0.05), total cholesterol (164.0 +/- 20.81 vs. 188.0 +/- 22.26 mg/dL, p=0.05) and LDL cholesterol (81.0 +/- 9.64 vs. 116.70 +/- 13.03 mg/dl, p=0.01). Differences between the other parameters were not significantly different. Acromegaly patients with high GH levels after an OGTT have much higher levels of homocysteine than patients with lower GH levels. The role of elevated homocysteine levels as an independent cardiovascular risk factor in the mortality of acromegaly patients should be determined in future studies.     

Homocysteine Thiolactone and Human Cholinesterases

1. The cholinergic system is important in cognition and behavior as well as in the function of the cerebral vasculature. 2. Hyperhomocysteinemia is a risk factor for development of both dementia and cerebrovascular disease. 3. Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are serine hydrolase enzymes that catalyze the hydrolysis of the neurotransmitter acetylcholine, a key process in the regulation of the cholinergic system. 4. It has been hypothesized that the deleterious effects of elevated homocysteine may, in part, be due to its actions on cholinesterases. 5. To further test this hypothesis, homocysteine and a number of its metabolites and analogues were examined for effects on the activity of human cholinesterases. 6. Homocysteine itself did not have any measurable effect on the activity of these enzymes. 7. Homocysteine thiolactone, the cyclic metabolite of homocysteine, slowly and irreversibly inhibited the activity of human AChE. 8. Conversely, this metabolite and some of its analogues significantly enhanced the activity of human BuChE. 9. Structure–activity studies indicated that the unprotonated amino group of homocysteine thiolactone and related compounds represents the essential feature for activation of BuChE, whereas the thioester linkage appears to be responsible for the slow AChE inactivation. 10. It is concluded that hyperhomocysteinemia may exert its adverse effects, in part, through the metabolite of homocysteine, homocysteine thiolactone, which is capable of altering the activity of human cholinesterases, the most pronounced effect being BuChE activation.     

Comparative Study on in Vitro Effects of Homocysteine Thiolactone and Homocysteine on HUVEC Cells: Evidence for a Stronger Proapoptotic and Proinflammative Homocysteine Thiolactone

Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. However the underlying mechanisms responsible for endothelial cell injury with increased plasma concentration of homocysteine or homocysteine derivatives remains still incompletely elucidated. In this study, we investigated the ability of homocysteine (Hcy) and homocysteine thiolactone (HcyT) to induce cell death and IL-8 secretion in primary human umbilical vein endothelial cells (HUVEC). Hcy and HcyT were both cytotoxic and capable of promoting cell death, as measured by caspase-3 activation and DNA fragmentation. ELISA assays clearly demonstrated that Hcy and HcyT strongly activated IL-8 release. Furthermore, our results showed that HcyT was much more efficient than Hcy in activating caspase-3 or in inducing IL-8 secretion. The use of antioxidants such as vitamin C and vitamin E strongly but not completely reduced programmed cell death and chemokine release suggesting that other pathways different than reactive oxygen species are also involved. This study suggests that Homocysteine derivatives like HcyT might possess stronger cytotoxicity and pro-inflammatory properties and that Hcy derivatives levels should therefore be more taken into account during diagnostics.     

Homocysteine biosynthesis pathways of Streptococcus anginosus

A gene (cgs) encoding cystathionine gamma-synthase was cloned from Streptococcus anginosus, and its protein was purified and characterized. The cgs gene and the immediately downstream lcd gene were shown to be cotranscribed as an operon. High-performance liquid chromatography analyses showed that the S. anginosus Cgs not only has cystathionine gamma-synthase activity, but also expresses O-acetylhomoserine sulfhydrylase activity. These results suggest that S. anginosus has the capacity to utilize both the transsulfuration and direct sulfhydrylation pathways for homocysteine biosynthesis.     

Homocysteine causes cerebrovascular leakage in mice

Elevated plasma homocysteine (Hcy) is associated with cerebrovascular disease and activates matrix metalloproteinases (MMPs), which lead to vascular remodeling that could disrupt the blood-brain barrier. To determine whether Hcy administration can increase brain microvascular leakage secondary to activation of MMPs, we examined pial venules by intravital video microscopy through a craniotomy in anesthetized mice. Bovine serum albumin labeled with fluorescein isothiocyanate (BSA-FITC) was injected into a carotid artery to measure extravenular leakage. Hcy (30 microM/total blood volume) was injected 10 min after FITC-BSA injection. Four groups of mice were examined: 1) wild type (WT) given vehicle; 2) WT given Hcy (WT + Hcy); 3) MMP-9 gene knockout given Hcy (MMP-9-/- + Hcy); and 4) MMP-9-/- with topical application of histamine (10(-4) M) (MMP-9-/- + histamine). In the WT + Hcy mice, leakage of FITC-BSA from pial venules was significantly (P < 0.05) greater than in the other groups. There was no significant leakage of pial microvessels in MMP-9-/- + Hcy mice. Increased cerebrovascular leakage in the MMP-9-/- + histamine group showed that microvascular permeability could still increase by a mechanism independent of MMP-9. Treatment of cultured mouse microvascular endothelial cells with 30 microM Hcy resulted in significantly greater F-actin formation than in control cells without Hcy. Treatment with a broad-range MMP inhibitor (GM-6001; 1 microM) ameliorated Hcy-induced F-actin formation. These data suggest that Hcy increases microvascular permeability, in part, through MMP-9 activation.     

Homocysteine to Hydrogen Sulfide or Hypertension

Hyperhomocysteinemia, an increased level of plasma homocysteine, is an independent risk factor for the development of premature arterial fibrosis with peripheral and cerebro-vascular, neurogenic and hypertensive heart disease, coronary occlusion and myocardial infarction, as well as venous thromboembolism. It is reported that hyperhomocysteinemia causes vascular dysfunction by two major routes: (1) increasing blood pressure and, (2) impairing the vasorelaxation activity of endothelial-derived nitric oxide. The homocysteine activates metalloproteinases and induces collagen synthesis and causes imbalances of elastin/collagen ratio which compromise vascular elastance. The metabolites from hyperhomocysteinemic endothelium could modify components of the underlying muscle cells, leading to vascular dysfunction and hypertension. Homocysteine metabolizes in the body to produce H₂S, which is a strong antioxidant and vasorelaxation factor. At an elevated level, homocysteine inactivates proteins by homocysteinylation including its endogenous metabolizing enzyme, cystathionine γ-lyase. Thus, reduced production of H₂S during hyperhomocysteinemia exemplifies hypertension and vascular diseases. In light of the present information, this review focuses on the mechanism of hyperhomocysteinemia-associated hypertension and highlights the novel modulatory role of H₂S to ameliorate hypertension.     

Regulation of Homocysteine Biosynthesis in Salmonella typhimurium

The regulation of the homocysteine branch of the methionine biosynthetic pathway in Salmonella typhimurium has been reexamined with the aid of a new assay for the first enzyme. The activity of this enzyme is subject to synergistic feedback inhibition by methionine plus S-adenosylmethionine. The synthesis of all three enzymes of the pathway is regulated by noncoordinate repression. The enzymes are derepressed in metJ and metK regulatory mutants, suggesting the existence of regulatory elements common to all three. Experiments with a methionine/vitamin B(12) auxotroph (metE) grown in a chemostat on methionine or vitamin B(12) suggested that the first enzyme is more sensitive to repression by methionine derived from exogenous than from endogenous sources. metB and metC mutants grown on methionine in the chemostat did not show hypersensitivity to repression by exogenous methionine. Therefore, it appears that the metE chemostat findings are peculiar to the phenotype of this mutant; such evidence suggests a possible role for a functional methyltetrahydrofolate-homocysteine transmethylase in regulating the synthesis of the first enzyme. Thus there appear to be regulatory elements which are common to the repression of all three enzymes, as well as some that are unique to the first enzyme. The nature of the corepressor is not known, but it may be a derivative of S-adenosylmethionine. metJ and metK mutants of Salmonella have a normal capacity for S-adenosylmethionine synthesis but may be blocked in synthesis or utilization of a corepressor derived from it.     

Homocysteine metabolism and its role in pathology

Results of the study of homocysteine metabolism and its role in physiological and pathological processes are given in this review. The participation of homocysteine in the process of methionine synthesis, transsulfuration, formation of homocysteine thiolacton and their regulation, polymorphism of homocysteine metabolism enzymes, the ways of homocysteine and thiolactone incorporation into protein molecule, sources and forms of homocysteine in the blood plasma, the role of hyperhomocysteinemia in pathogenesis of cardiovascular and other diseases have been considered. Principles of homocysteine determination in the blood plasma are described here.     

高效液相测定同型半胱氨酸方法的建立

为测量包括同型半胱氨酸在内的 1 8种氨基酸 ,用高效液相紫外检测法 ,在氨基酸混合标样中 ,加进Hcy标准品 ,仍用 4 5min程序分析 ,对AccqTag方法进行了修改 ,衍生温度改为常温 ,衍生后用醋酸酸化 ,并保存于 0～ 1℃ ,同型半胱氨酸出峰的时间为第 33min左右 ,结果得到了分离良好的 1 8种氨基酸图谱。     

同型半胱氨酸与不同类型卒中的相关性研究

目的：探讨同型半胱氨酸（Hcy）与不同类型脑卒中的关系,并对高Hcy血症成因作初步分析。方法：测定225例缺血性脑卒中和40例出血性脑卒中患者以及85例同龄健康受试者的血浆Hcy水平以及叶酸、维生素B12的浓度,将缺血性卒中按照TOAST分型分为不同临床亚组--动脉粥样硬化性脑血栓形成组,腔隙性脑梗死组,心源性脑栓塞组以及其他或不明原因脑梗死组,并分别与健康组进行对照研究。结果：血浆同型半胱氨酸平均水平在动脉粥样硬化性脑梗死组患者为（16.19±4.35）μmol/L,腔隙性脑梗死患者为（16.89±6.41）μmol/L,心源性脑栓塞组为（18.23±4.83）μmol/L,其他或不明原因脑梗死患者为（17.31±2.56）μmol/L,脑出血组患者为（14.91±4.54）μmol/L,均高于对照组（7.20±7.91）μmol/L,P〈0.05;各缺血性卒中组间同型半胱氨酸水平差异无显著性（P〈0.05）;缺血性卒中组患者血浆同型半胱氨酸水平高于出血性卒中组（P〈0.05）。卒中各组叶酸和维生素B12浓度均显著低于对照组（P〈0.05）。结论：血浆同型半胱氨酸在不同类型卒中中均升高,高血浆Hcy水平可能是脑卒中的独立危险因素,叶酸和VitB12缺乏可能是导致高Hcy血症的重要原因。     

Homocysteine and oxidative modification of plasma proteins

Summary The oxidative status of plasma proteins after incubation with elevated homocysteine levels has been examined in the presence and absence of transition metal ions. 200µM homocysteine alone does not provoke any loss of plasma thiols groups, but their oxidation significantly enhances as copper concentration increases. No plasma proteins carbonyl groups enhancement has been concurrently found.The physiological relevance of the study is discussed in relationship with the metal-catalyzed oxidation system increment connected with age and nutritional deficiences.     

Homocysteine and cognitive function in elderly people

DEMENTIA IS HIGHLY PREVALENT AMONG ELDERLY PEOPLE, and projections show that the number of people affected might triple over the next 50 years, mainly because of a large increase in the oldest-old segment of the population. Because of this and the disease''s devastating effects, measures for the prevention and early detection of dementia are crucial. Age and years of education are among the most relevant risk factors for dementia, but in recent years the role of homocysteine has also been investigated. Homocysteine is an amino acid produced in the metabolism of methionine, a process dependent on the B vitamins cobalamin, vitamin B₆ and folic acid. There is evidence that increased serum homocysteine levels are associated with declining cognitive function and dementia. We review this evidence in addition to the potential mechanisms through which homocysteine acts on the brain to cause cognitive dysfunction, the metabolism of homocysteine and factors associated with alteration of the normal metabolism. Dementia is characterized by a progressive deterioration of cognitive skills that leads to a decline in the ability to perform daily activities. It affects 8% of people over the age of 65¹ and results in more than 60 000 new cases in Canada each year. Alzheimer''s disease accounts for more than 50% of cases of dementia in Canada.² Projections for the next 50 years show that the number of patients with dementia might triple,³ mainly because of a large increase in the oldest-old segment of the population. Because of the disease''s high prevalence and devastating effects on patients, caregivers and the health care system, measures for the prevention and early detection of dementia are crucial.Age and years of education are among the most relevant risk factors for dementia, but in recent years the role of homocysteine has also been investigated. Homocysteine is an amino acid that is produced in the metabolism of methionine, a process dependent on the B vitamins cobalamin, vitamin B₆ and folic acid. There is evidence that increased serum homocysteine levels are associated with declining cognitive function and dementia. We review this evidence in addition to the potential mechanisms through which homocysteine acts on the brain to cause cognitive dysfunction, the metabolism of homocysteine and factors associated with alteration of the normal metabolism.