同型半胱氨酸化与疾病

高同型半胱氨酸血症能引起多种疾病如动脉粥样硬化、恶性肿瘤、神经退行性疾病等。研究发现,同型半胱氨酸(homocysteine,Hcy)能诱导氧化应激、内质网应激、蛋白质聚集。然而,具体的分子机制还有待进一步研究。近年来,蛋白质的同型半胱氨酸化引起广泛关注,本文对Hcy的代谢途径、同型半胱氨酸化及对机体的影响予以综述。     

高同型半胱氨酸对动脉粥样硬化形成的作用

同型半胱氨酸是甲硫氨酸的中间代谢产物,高同型半胱氨酸血症已成为动脉粥样硬化的一种独立危险因素,探讨高同型半胱氨酸血症形成的原因及同型芈胱氨酸致动脉粥样硬化的机制,有助于动脉粥样硬化的防治.     

胱抑素C与心血管疾病的关系

胱抑素C(Cystatin C)是一种低分子量的分泌性蛋白质,与肾小球滤过率(GFR)密切相关,是肾小球滤过功能的一个理想指标。作为一种半胱氨酸蛋白酶抑制剂,胱抑素C与同型半胱氨酸、组织蛋白酶等相互作用,而参与了动脉粥样硬化、动脉瘤及心肌梗塞等心血管疾病的病理过程。     

同型半胱氨酸：动脉粥样硬化的一个独立的危险因素

同型半胱氨酸是蛋氨酸和半胱氨酸代谢过程中的一个重要中间产物。血浆中同型半胱氨酸的浓度与遗传因素和营养因素有关。与同型半胱氨酸代谢有关的Ｎ＾５Ｎ＾１０－亚甲基四氢叶酸还原酶（ＭＴＨＦＲ）和胱硫醚－β－合成酶（ＣＢＳ）的基因突变,酶活性下降,引起的高同型半胱氨酸血症,可能是动脉粥样硬化等心血管病发病的一个独立的危险因素。     

同型半胱氨酸在心血管疾病中的免疫调节作用

高同型半胱氨酸血症是动脉粥样硬化的独立危险因子,但是其致病机制尚未完全阐明。本文将从体液免疫、单核巨噬细胞以及T细胞活性等几方面归纳总结同型半胱氨酸在心血管疾病中的免疫调节作用。同型半胱氨酸可以诱导单核细胞和T细胞分泌趋化因子和细胞因子,还可以直接刺激B细胞增殖及IgG分泌。此外,本文还总结了高同型半胱氨酸致炎作用的细胞内机制。同型半胱氨酸可以直接或间接导致氧化应激或者内质网应激,还可以降低一氧化氮的生物活性,影响包括S-腺苷蛋氨酸和S-腺苷同型半胱氨酸的水平,从而导致心血管疾病的发生。     

同型半胱氨酸对蛋白质的修饰作用研究进展

高同型半胱氨酸血症在心血管疾病、孕期并发症、认知障碍和骨质疏松症等疾病发生发展过程中是一个独立的危险因子,同型半胱氨酸的致病机制相关研究一直受到科研工作者的广泛关注.本综述主要介绍新近国际科研界热点,即以蛋白质同型半胱氨酸化为中心的假设理论.该理论以同型半胱氨酸的分子化学性质为基础,通过两种基本的蛋白质修饰途径,较好地解释了蛋白质的结构和功能损伤之间的关系,而这种对蛋白质的修饰所造成的血管性损伤也许正是引起上述多种不甚相关疾病的共同关键机制.     

血浆同型半胱氨酸水平升高与动脉粥样硬化

心血管疾病已成为当今全球性致残与致死的最重要原因之一。目前确定的冠心病的危险因素主要包括高龄、血脂异常、高血压、糖尿病、吸烟、肥胖症。大量的临床试验及流行病学研究已经证实血浆同型半胱氨酸水平升高是心血管疾病的一个独立的危险因素。健康人的血浆同型半胱氨酸水平为5～10μmol／L。血浆同型半胱氨酸水平严重升高的主要原因是胱硫醚-β-合成酶(cystathionine-β-synthase,CBS)基因的缺陷。CBS基因缺陷的纯合体可导致血浆同型半胱氨酸水平升高至100～500μmol／L。血浆同型半胱氨酸水平严重升高的病人通常伴随神经系统异常、早发性的动脉粥样硬化。叶酸、维生素B6和B12治疗能降低血浆同型半胱氨酸的水平并改善血管内皮功能、减少经皮冠状动脉腔内成形术(percutaneou stransluminal coronary angioplasty,PTCA)术后并发症。迄今为止,血浆同型半胱氨酸水平升高引起心血管疾病的发病机制并未完全明了,目前认为主要与以下几个方面有关：(1)内皮细胞损伤及功能障碍。我们实验室在CBS基因敲除的小鼠模型上证实血浆同型半胱氨酸水平升高能抑制eNOS的活性,导致主动脉内皮功能的障碍。我们还在细胞模型上证实了同型半胱氨酸能显著抑制内皮细胞的增殖。(2)KH固醇和甘油三脂生物合成代谢异常。我们实验室在apoE、CBS双基因敲除的小鼠模型上证实血浆同型半胱氨酸水平升高能改变肝脏的脂肪代谢,增加巨噬细胞对修饰LDL的摄取,从而导致胆固醇脂和甘油三脂在血管壁的堆积,促进主动脉粥样斑块的形成。(3)刺激血管平滑肌细胞增殖。此外还发现同型半胱氨酸能激活蛋白激酶C信号途径,促进胶原蛋白的合成,抑制弹性蛋白和胶原蛋白的交联。(4)激活血栓形成。(5)激活单核细胞。目前认为同型半胱氦酸主要通过以下几个化学机制致病;(1)自氧化产生活性氧。同型半胱氨酸在自氧化的过程中能产生大量的活性氧,从而引起血液中脂蛋白和细胞膜脂质的过氧化损伤,并进一步引起内皮功能的障碍。(2)在腺苷的参与下形成SAH,一种甲基转移抑制剂,导致细胞内的低甲基化。(3)与一氧化氮结合形成亚硝酰物。(4)参与蛋白质的合成。总之,我们和其他实验室的研究结果均表明同型半胱氨酸不仅与动脉粥样硬化相关,而且具有致病效应。尽管补充叶酸、维生素B6和B12等治疗能降低血浆同型半胱氨酸的水平,但是否能降低心血管疾病的风险仍有待于大量的动物研究及临床试验。     

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。     

高同型半胱氨酸血症致动脉粥样硬化的细胞分子机制

同型半胱氨酸（homocysteine,Hcy)是蛋氨酸代谢途径产生的含硫氨基酸,其代谢紊乱可以诱导高同型半胱氨酸血症的发生,已被临床及流行病学资料证实为动脉粥样硬化发病的独立危险因子。Hcy通过激活二酰甘油－蛋白激酶C－（DAG－PKC）及丝裂素活化蛋白激酶（MAPK）途径,诱导相关基因的表达,促进细胞钙化,启动脂质过氧化应激,从而损伤心血管系统。金属硫蛋白,牛磺酸,L－精氨酸作为内源性小分子物质,成为继维生素B6,B12之后控制和治疗高同型半胱氨酸血症的新途径。     

高龄老年人同型半胱氨酸水平的临床分析

目的:探讨高龄老年人与正常人群之间同型半胱氨酸水平差异。方法:选择2011年10月至2012年7月在我科住院,年龄大于80岁,生活能够自理,无严重疾病的患者88例为研究对象,检测其血清同型半胱氨酸水平,利用SPSS17.0软件统计高龄老年人同型半胱氨酸水平,并比较不同性别的高龄老人血清同型半胱氨酸水平的差异,以及其与普通人群之间的差异。结果:高龄老年人同型半胱氨酸水平近正态分布,其水平在8.5～66.6μmol/L之间,均值为18.10±0.99μmol/L,高于正常值(5～15μmol/L),95%的置信区间为16.13～20.06μmol/L。其中高龄男性同型半胱氨酸水平在10～66.6μmol/L之间,均值为19.40±1.23μmol/L,95%的置信区间为16.94～21.87μmol/L;女性同型半胱氨酸水平在8.5～29.2μmol/L,均值为14.12±0.98μmol/L,95%的置信区间为12.09～16.15μmol/L;男性血清同型半胱氨酸显著高于女性(P<0.01)。结论:高龄老年人血清中同型半胱氨酸水平较正常值偏高,且高龄男性血同型半胱氨酸水平显著高于高龄女性。     

2型糖尿病患者血糖漂移水平与动脉脉搏波速度的相关性研究

目的:研究2型糖尿病患者血糖漂移水平与动脉脉搏波速度的关系。方法:共入选82例2型糖尿病患者作为研究对象。所有研究对象应用自动脉搏波速度测定仪测定颈动脉-股动脉脉搏波速度(CFPw V);采用动态血糖检测系统(CGMS)及全自动生化分析仪进行检测,收集空腹血糖(FBG)、餐后2小时血糖(2hPG)、糖化血红蛋白(HbA1c)、血糖水平标准差(SDBG)、平均血糖波动幅度(MAGE)、最大血糖波动幅度(LAGE)、昼间血糖漂移幅度(MODD)等血糖参数。根据CGMS检测结果将82例2型糖尿病患者分为血糖低漂移组(47例)和血糖高漂移组(35例),比较两组中各血糖参数及CFPw V水平,计算两组动脉硬化发生率,并将各血糖参数与CFPw V进行Pearson相关性分析。结果:与血糖低漂移组比较,2hPG、SDBG、MAGE、LAGE、MODD、CFPw V在血糖高漂移组中升高(P0.05);血糖高漂移组中动脉硬化的发生率高于血糖低漂移组(P0.05);Pearson相关性分析分析显示2hPG、MAGE、LAGE、MODD与CFPw V相关(P0.05)。结论:本研究中,82例2型糖尿病患者存在不同程度的动脉硬化;2hPG、MAGE、LAGE、MODD是2型糖尿病患者CFPw V升高的相关因素,提示血糖漂移进一步加重动脉硬化,参与动脉硬化的发生发展。应该重视对血糖漂移的控制,减少动脉硬化的发生率,延缓动脉硬化的发展。     

脑梗死患者颈动脉粥样硬化的相关因素分析

目的:探讨脑梗死患者颈动脉粥样硬化的危险因素。方法:选取148例脑梗死患者作为实验组和同期住院的80例非脑梗死疾病患者为对照组,检测并比较各组年龄、吸烟、血压、饮酒、糖尿病、血脂、同型半胱氨酸和磷脂酶A2等指标,然后进行卡方检验、相关性和Logistic回归分析。结果:实验组颈动脉粥样硬化检出率为82.43%,对照组为12.5%,其差异具有统计学意义(P0.05)。高龄、吸烟、高血压、高血脂、高同型半胱氨酸血症、高磷脂酶A2(LP-PLA2)血症是经动脉粥样硬化的危险因素,且血浆同型半胱氨酸水平、LP-PLA2水平、血压与颈动脉斑块稳定性有关(P0.05)。结论:颈动脉粥样硬化是脑梗死的病理基础,与高龄、吸烟、高血压、高血脂、高同型半胱氨酸血症、高磷脂酶A2(LP-PLA2)血症有关,对高同型半胱氨酸血症、LP-PLA2和高血压患者要关注其斑块的稳定性。     

2 型糖尿病患者肝损伤标志物与下肢动脉病变的相关性分析

目的：探讨2 型糖尿病患者肝损伤标志物水平与其下肢动脉病变的相关性,为2 型糖尿病并发症的防治提供参考依据。方 法：选取我院收治的2 型糖尿病患者946 例,根据下肢动脉内膜中层厚度分为以下3 组,即无动脉硬化组(276 例)、单纯性动脉硬 化组(598 例)和动脉硬化伴管腔狭窄或闭塞组(72 例)。分析和比较三组之间肝损伤标志物谷丙转氨酶(ALT)、谷草转氨酶(AST)、γ-谷氨酰转肽酶(GGT)水平的差异,及其与2型糖尿病患者下肢动脉硬化程度的相关性。结果：随着动脉硬化程度的加重,2 型糖尿病患者的ALT 水平逐渐升高,三组之间两两比较差异均有统计学意义(P<0.05)。动脉硬化伴管腔狭窄或闭塞组AST 水平显著高于非动脉硬化组和单纯性下肢动脉硬化组,而动脉硬化组和非动脉硬化组之间AST 水平比较无显著差异(P>0.05)。三组之间γ-谷氨酰转肽酶水平比较无显著性差异(P>0.05)。Spearman 等级相关分析显示ALT 与糖尿病下肢动脉硬化的相关系数为0.30484。结论：2型糖尿病患者ALT 水平与其下肢动脉硬化程度显著相关。     

Association between smoking status and homocysteine levels and possible effect modification by cholesterol and oestradiol

Abstract

Introduction: This study aimed to examine the association of smoking status with homocysteine levels and to determine whether the association is modified by oestradiol or cholesterol.

Methods: Data (N?=?4580) were obtained from National Health and Nutrition Examination Survey 2003–2004 with analysis done in 2018 on adults aged ≥20 years. The outcome was homocysteine; smoking status was the exposure variable and categorized as current, former or never smoker. Generalized linear models were used to examine the associations between smoking status and homocysteine levels, while assessing the impact of oestradiol and cholesterol.

Results: After adjusting for age, sex, ethnicity, education and income level, homocysteine levels did differ by smoking status ((current smokers versus never smokers: β: 0.18?CI: 0.00, 0.36), (former smokers: β: 0.10?CI: –0.09, 0.28)). The addition of oestradiol as an interaction term in adjusted models was associated with a 16.6% increase in homocysteine levels when compared to models without the interaction term. Oestradiol but not cholesterol did moderate the association between smoking status and homocysteine levels.

Discussion and conclusions: Homocysteine levels did differ across smoking status after adjusting for confounders. Oestradiol did moderate the relationship between homocysteine and smoking status.     

Anti-angiogenic effects of homocysteine on cultured endothelial cells

High levels of homocysteine induce a sustained injury on arterial endothelial cells which accelerates the development of thrombosis and atherosclerosis. Some of the described effects of homocysteine on endothelial cells are features shared with an anti-angiogenic response. Therefore, we studied the effects of homocysteine on key steps of angiogenesis using bovine aorta endothelial cells as a model. Homocysteine decreased proliferation and induced differentiation. Furthermore, 5 mM homocysteine produced strong inhibitions of matrix metalloproteinase-2 and urokinase, two proteolytic activities that play a key role in extracellular matrix re-modeling, and decreased migration and invasion, other two key steps of angiogenesis. This study demonstrates that homocysteine can inhibit several steps of the angiogenic process.     

Homocysteine pre-treatment increases redox capacity in both endothelial and tumor cells

Objective: We studied the modulatory effects of homocysteine pre-treatment on the disulfide reduction capacity of tumor and endothelial cells.

Methods: Human MDA-MB-231 breast carcinoma and bovine aorta endothelial cells were pre-treated for 1–24 hours with 0.5–5 mM homocysteine or homocysteine thiolactone. After washing to eliminate any rest of homocysteine or homocysteine thiolactone, cell redox capacity was determined by using a method for measuring disulfide reduction.

Results: Homocysteine pre-treatments for 1–4 hours at a concentration of 0.5–5 mM increase the disulfide reduction capacity of both tumor and endothelial cells. This effect cannot be fully mimicked by either cysteine or homocysteine thiolactone pre-treatments of tumor cells.

Discussion: Taken together, our data suggest that homocysteine can behave as an anti-oxidant agent by increasing the anti-oxidant capacity of tumor and endothelial cells.     

同型半胱氨酸水平与女性绝经期骨质疏松相关性研究

目的:通过分析女性绝经期不同骨密度人群的血浆同型半胱氨酸(HCY)指标,探讨同型半胱氨酸在女性绝经期骨质疏松发生过程中的作用及其潜在的临床价值。方法:收集2014年3月至2016年3月我院体检中心进行体检的女性绝经期妇女(60岁)血样标本共计625例,根据体检的骨密度报告对其进行分组,骨质疏松组215例,骨量减少组309例,骨量正常组101例,测量每组的同型半胱氨酸水平。结果:骨密度程度与同型半胱氨酸水平存在负相关关系(rs=-0.763,P=0.046),三组之间的同型半胱氨酸水平也存在显著差异(F=4.807,P0.016),其中骨质疏松组指标最高,骨量正常组指标最低。结论:同型半胱氨酸是重要的骨代谢指标,在衡量绝经期妇女骨质疏松进展中具有重要的意义。     

Homocysteine Induces Iron-Catalyzed Lipid Peroxidation of Low-Density Lipoprotein that is Prevented by Alpha-Tocopherol

Homocystinuria is an inborn error of methionine metabolism that is characterized by the premature development of arteriosclerosis. As one of the major factors in the pathogenesis of arteriosclerosis, modification of low-density lipoprotein (LDL) has received widespread attention by many investigators. In this study, to elucidate the relationship between elevated homocysteine levels and premature arteriosclerosis, we investigated the role of homocysteine in the iron-catalyzed oxidative modification of LDL. When LDL isolated from a healthy subject was incubated with homocysteine and ferric ion, a gradual decrease of polyunsaturated fatty acids (PUFA), formation of thiobarbituric acid-reactive substances (TBARS) and fluorescent substances, and the fragmentation of apoprotein B (apoB) were observed. The extent of oxidative modification was dependent on the concentration of homocysteine. Modification of LDL was suppressed until the remaining α-tocopherol concentration reached a critical level. When the α-tocopherol content of LDL was increased by 2.6-fold, both the formation of TBARS and the fragmentation of apoB were suppressed. These results suggest that homocysteine might promote iron-catalyzed oxidation of LDL and imply its role for the development of premature arteriosclerosis.     

Elevated homocysteine level and prognosis in patients with acute coronary syndrome: a meta-analysis

Objective: Controversial results exist with respect to the association between elevated homocysteine level and adverse prognosis in acute coronary syndrome (ACS) patients. We performed a meta-analysis to evaluate the prognostic value of homocysteine level on ACS patients.

Materials and methods: A comprehensive literature search of PubMed and Embase databases was conducted prior to August 2018. Prospective observational studies reporting the association of baseline homocysteine level with major adverse cardiovascular events (MACE), cardiovascular or all-cause mortality in ACS patients were selected. Pooled risk ratio (RR) and corresponding 95% confidence intervals (CI) were calculated for the highest versus the lowest homocysteine level.

Results: Ten studies including 4120 ACS patients were identified. ACS patients with the highest homocysteine level had an increased risk of MACE (RR 2.01; 95% CI 1.53–2.64) and all-cause mortality (RR 2.05; 95% CI 1.50–2.79) after controlling confounding factors. However, the association between elevated homocysteine level and cardiovascular mortality (RR 1.08; 95% CI 0.83–1.39) was not statistically significant.

Conclusions: Elevated homocysteine level was associated with an increased risk of MACE and all-cause mortality among ACS patients. However, the association of elevated homocysteine level with cardiovascular mortality in ACS patients should be further confirmed in future studies.     

下肢动脉粥样硬化致双下肢水肿的临床观察

目的:探讨淋巴结肿大在下肢动脉粥样硬化致双下肢水肿发病中的作用。方法:选择经超声诊断有下肢动脉粥样硬化伴腹股沟淋巴结肿大、双下肢水肿患者20例作为观察组,22例有下肢动脉硬化但无腹股沟淋巴结肿大、双下肢水肿者作为对照组,比较其动脉粥样斑块、淋巴结大小及胆固醇、血沉、C-反应蛋白水平的差异。结果:观察组斑块、淋巴结大小均大于对照组,胆固醇、血沉、C-反应蛋白水平均高于对照组。结论:下肢动脉粥样硬化伴腹股沟淋巴结肿大者可致双下肢水肿。