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同型半胱氨酸与心血管疾病相关性研究进展

2024-05-20刘志强孙经武董文敬张翠

中国医学创新 2024年11期
关键词:同型半胱氨酸心血管疾病氧化应激

刘志强 孙经武 董文敬 张翠

【摘要】 近年来,随着经济水平的提高及生活方式的改变,心血管疾病(cardiovascular disease,CVD)的发生率呈逐年上升趋势。CVD与许多危险因素相关,如高血压、糖尿病等,同型半胱氨酸(homocysteine,Hcy)水平与CVD的发生、发展也有着密切的关系。现如今,高同型半胱氨酸血症(hyperhomocysteinemia,HHcy)已成为导致CVD新的独立危险因素,且相关致病机制复杂而多样。本文就Hcy相关知识点、致病机制及与CVD的研究进展进行系统综述。

【关键词】 心血管疾病 同型半胱氨酸 高同型半胱氨酸血症 氧化应激 高血压

Research Progress on the Correlation between Homocysteine and Cardiovascular Disease/LIU Zhiqiang, SUN Jingwu, DONG Wenjing, ZHANG Cui. //Medical Innovation of China, 2024, 21(11): -180

[Abstract] In recent years, with the improvement of economic level and the change of lifestyle, the incidence of cardiovascular disease (CVD) is increasing year by year. CVD is associated with many risk factors, such as hypertension, diabetes mellitus, etc. Homocysteine (Hcy) level is also closely related to the occurrence and development of CVD. Nowadays, hyperhomocysteinemia (HHcy) has become a new independent risk factor of CVD, and relevant pathogenic mechanism is complex and diverse. In this paper, the related knowledge points, pathogenic mechanism of Hcy, and its research progress with CVD are systematically reviewed.

[Key words] Cardiovascular disease Homocysteine Hyperhomocysteinemia Oxidative stress Hypertension

First-author's address: Department of Cardiology, Binzhou Medical University Affiliated Hospital, Binzhou 256603, China

doi:10.3969/j.issn.1674-4985.2024.11.038

隨着全球环境、生活方式的改变及医疗水平的发展,心血管疾病(CVD)流行病学也发生了转变,从主要发生在发达国家转变为全球性疾病,现已成为我国患病率最高的一组疾病。CVD及其相关并发症是导致患者死亡的最主要原因,CVD致病因素诸多,其中吸烟、血脂异常、高血压、糖尿病、腹型肥胖和社会心理因素等对CVD的影响较大[1]。大量研究证据表明,同型半胱氨酸(Hcy)是CVD的独立危险因素之一,血浆Hcy浓度升高与CVD的发生概率增加相关[2],并且强调心肌对Hcy造成的损伤是唯一敏感的。本文就Hcy的概述及其与CVD(高血压、心力衰竭、冠心病)的相关性进行综述,以期为临床治疗提供参考。

1 Hcy的概述

1.1 Hcy的概念

半胱氨酸是脂肪族含巯基的极性α-氨基酸,是人体的条件必需氨基酸和生糖氨基酸,由体内的甲硫氨酸转化而来,而Hcy是人体中一种非必需的含硫氨基酸,因其化学性质与半胱氨酸相似而得名。Hcy存在于甲硫氨酸和半胱氨酸代谢过程中,主要来源于甲硫氨酸(甲硫氨酸是一种从膳食蛋白质中获取的必需氨基酸)。Hcy和硫化氢(H2S)的水平是相互调节的,当Hcy(5~15 μmol/L)和半胱氨酸均在生理浓度条件下,大约70%的H2S是由半胱氨酸产生的,然而,在Hcy过度升高时,Hcy取代半胱氨酸成为高同型半胱氨酸血症(HHcy)中H2S的重要来源[3]。

1.2 Hcy的合成与代谢

Hcy的合成:甲硫氨酸携带着S-CH3,参与甲基的转移。在腺苷转移酶的催化作用下,甲硫氨酸与腺苷三磷酸(ATP)相反应,生成S-腺苷甲硫氨酸(SAM)[4]。SAM脱甲基化后,转化成S-腺苷同型半胱氨酸(SAH),随后发生水解,脱去腺苷,生成Hcy。正常情况下,Hcy维持在5~15 μmol/L,16~30 μmol/L为略高水平,31~100 μmol/L为中等水平,>100 μmol/L定义为严重HHcy。

Hcy的代谢:Hcy主要通过两条途径代谢。(1)转甲基化途径(甲硫氨酸缺乏):一部分Hcy在叶酸和维生素B12及甲硫氨酸合成酶的催化作用下,转甲基化合成甲硫氨酸[5];(2)转硫途径(甲硫氨酸丰富):另外的Hcy在胱硫醚β合成酶的催化下不可逆的生成半胱氨酸和α酮丁酸[6]。酶促反应产生的H2S,主要来源于含硫氨基酸的代谢,特别是半胱氨酸和Hcy。Hcy是内源性H2S产生的前体,越来越多的研究表明内源性H2S的产生和代谢与Hcy密切相关[7]。

2 Hcy的致病机制

2.1 致内皮细胞损伤

Hcy是一种氨基酸,血浆中浓度升高会引起内皮细胞损伤。内皮功能障碍可以被定义为血管舒张和收缩之间的内稳态平衡破坏。在血管内皮表面,促凝血因子和抗凝因子维持在相对平衡的状态,Hcy水平升高可打破此平衡,使血管内皮表面从抗凝变为促凝状态,最终造成了内皮细胞的损伤[8]。

研究发现,一氧化氮(NO)合成酶的表达可以被Hcy抑制,导致NO的产生减少,从而触发内皮细胞的损伤,影响血管舒张[9]。同时,Djuric等[10]发现Hcy增加会激活NADPH氧化酶不同亚型的表达,导致超氧阴离子自由基含量增加,进而导致NO的生物利用度降低。Moretti等[11]研究发现,HHcy使NO生物利用度降低,引起细胞完整性的破坏,从而造成内皮功能障碍,导致内皮依赖的舒张受损,促进炎症反应。Haloul等[12]研究显示,HHcy伴发的血管功能障碍的主要发病机制是NO介导的血管舒张功能受损,并且高浓度的Hcy可能是病态肥胖个体血管功能障碍的独立预测因子。

Ahmad等[13]发现,冠状动脉微血管内皮功能障碍(coronary microvascular endothelial dysfunction,CMED)与血清Hcy水平呈正相关,即Hcy水平升高与CMED诊断概率显著增加相关;而Esse等[14]研究发现过量的S-腺苷高半胱氨酸(S-adenosine homocysteine,AdoHcy)所造成的细胞低甲基化也是Hcy诱导血管毒性的分子基础(AdoHcy作为Hcy的前体,可在HHcy的背景下蓄积,而低甲基化可影响细胞的发育与分化等功能)。Ahmad等[13]在先前的观察结果上又有了新的研究进展,并证明HHcy通过影响冠状血管扩张/收缩直接导致内皮功能障碍。因此可以得出Hcy水平升高介导的CVD可能与冠状动脉内皮功能障碍有关。

2.2 致氧化应激

氧化应激是由于体内氧化和抗氧化系统平衡的破坏,氧化水平超过氧化清除的速度,最终造成组织损伤。Joseph等[15]研究表明,HHcy对心肌产生直接不良影响是通过促氧化机制。HHcy可通过生成活性氧(ROS)或通过损害相关的抗氧化系等多种分子机制诱导氧化应激[16]。Hcy通过二硫键与血浆蛋白(主要是白蛋白)、其他低分子血浆硫醇或第二个Hcy分子结合时,在Hcy游离巯基氧化过程中产生ROS活性氧[17]。

Hcy的巯基基团增加氧化应激,主要是通过作为促氧化剂分子参与反应。此外,Hcy的巯基基团在形成二硫键的过程中,损害蛋白质的功能并导致内质网产生应激[18]。氧化应激可导致炎症途径的激活[19],从而释放多种炎症因子,使血管内部发生损伤。HHcy也能够影响体内甲基化过程,从而抑制H2S的生成,H2S有多种作用,并通过多种途径发挥其作用,但其主要途径与氧化应激和NO相关[20]。在一项临床研究中,伴有HHcy的冠状动脉疾病患者,其整体DNA呈甲基化状态[21],且整体超甲基化与血浆Hcy水平呈显著正相关。Hcy影响了体内甲基化过程,从而使得H2S含量下降,导致血管受损。通过各种研究表明,可得出Hcy可诱导氧化还原稳态的破坏。

2.3 促进动脉粥样硬化(AS)

AS是一种以内皮功能障碍为特征的慢性炎症性疾病。内皮祖细胞(EPCs)可参与血管损伤后的修复,并抑制内皮损伤,降低AS风险[22]。Ahmad等[13]研究显示冠状动脉粥样硬化的早期与Hcy水平升高相关,并证实了血清Hcy水平与冠状动脉微血管内皮功能损伤(早期AS的一个特征)之间的明确相关性。Butkowski等[23]研究中,发现Hcy升高通过损伤内皮功能、增加氧化应激和诱导血栓形成等促进AS。Hcy浓度升高可改变血管内皮功能,其表面特征从抗凝变为促凝状态,从而导致脂质沉积,促进AS[24]。Hcy通过诱导白细胞介素-6(IL-6)、白细胞介素-8(IL-8)、肿瘤坏死因子-α(TNF-α)表达的上调及参与内皮炎症和下调血管重塑过程的组织蛋白酶(如细胞外调节蛋白激酶、磷酸激酶B等),从而影响IL-6和TNF-α及增强VEGF/ERK1/2信号传导途径,直接作用于内皮,这在AS过程中是不变的[25]。有研究表明,血清Hcy可促进体内氧自由基的产生,从而破坏内皮细胞并影响其功能,并进一步导致血管内膜的增厚,最终导致AS的发生[14]。由此可见,Hcy升高可促进AS的发生,从而诱发CVD。

2.4 促进心脏重构

当心肌功能受到严重受损,心肌细胞或细胞外部分基质、胶原纤维结缔组织均会发生一系列变化,该过程称为心肌重构。在一项动物实验中,HHcy可抑制TGF-β1/Smad通路及H2S的生成,减弱H2S对血管平滑肌细胞增殖的抑制作用,进而造成自发性高血压大鼠的心肌纤维化[26],由此可见HHcy可导致心肌纤维化。Hcy是蛋白质转化和代谢的中间产物,作用于内皮细胞,造成血管功能异常,进而启动炎症反应,增强氧化应激,引起心肌肥大和间质纤维化,最终诱导心室重构[27-28]。

3 Hcy与CVD的关系

3.1 Hcy与高血压

目前我国高血压的患病率正在逐年增加,根据2018年的一项全国高血压调查,我国患高血压的总人数达2.44亿人,约每4个成人中就有一个是高血压患者[29]。全球高血压的患病率和绝对负担正在增加[30]。高血压的危险因素很多,诸如遗传、年龄、高钠饮食、生活方式,而HHcy也是其危险因素之一。在Deng等[31]的临床研究中發现,Hcy水平与高血压呈正相关,并且Hcy与高血压患者的心肌肥大呈正相关。HHcy引起的心肌肥大的原因尚未有确切的定论,可能与心脏中高Hcy引起的氧化应激和肥大细胞密度的增加有关,也可能是因为蛋白激酶C的激活和胶原蛋白代谢的改变[32]。Shi等[33]研究发现Hcy水平升高可能导致血压升高,其作用可能通过RAAS和ERK通路实现[33]。在急性心肌梗死(acute myocardial infarction,AMI)患者中,高Hcy与高血压具有相互促进的作用,研究显示,AMI伴有高血压、HHcy,会导致更为严重的冠脉病变,如血管堵塞、左室射血分数降低等[34]。

3.2 Hcy与心力衰竭(HF)

慢性充血性心力衰竭(chronic congestive heart failure,CCHF)是心室充盈和射血功能的受损,从而导致心室射血功能降低,导致全身供血不足。在一项居民调查研究中,长期暴露于H2S使Hcy水平增加与心力衰竭死亡率和发病率增加相关[35]。在无缺血或充血性心力衰竭(CHF)病史的老年人群中,中重度HHcy与CVD事件和全因死亡显著相关。在男性中,这种正相关性很明显[36]。Kim等[8]研究证明CHF患者的Hcy水平与病情进展呈正相关。

血清Hcy水平与心功能相关指标的相关性研究分析显示,血清Hcy与左心室舒张末期内径(left ventricular end diastolic diameter,LVEDD)呈正相关,并与左室射血分数呈负相关[37]。这一结论在Hu等[27]研究中也得到了证实,其研究结果显示,与正常人群相比,CCHF患者血清Hcy明显升高,纽约心脏病协会(NYHA)分级越高,病情越重,血清Hcy水平越高。同样,在Jin等[38]研究,HF患者Hcy水平高于健康对照组,且与NYHA分级的提高呈正相关,证实了血浆Hcy水平和HF有密切和显著的相关性。结合相关试验及临床研究,我们发现血浆Hcy水平升高会导致氧化应激,心肌组织中过量的ROS蓄积,从而引起细胞功能障碍,在某些情况下甚至引起细胞死亡(在心肌细胞中尤为明显),影响心肌重塑的发生和進展,从而导致HF[39]。

3.3 Hcy与冠心病

冠心病是冠状动脉粥样硬化性心脏病的简称,是一种缺血性心脏病。HHcy通过基质金属蛋白酶-9(MMP-9)表达上调导致AS和AS血栓形成,这是AS斑块不稳定甚至破裂的原因[11]。Bosevski等[40]研究证实,Hcy水平与CAD之间存在正相关,并证明了其在AS发展中的可能作用。Tian等[41]研究表明,在CAD合并HHcy的病例中,H2S在细胞中蓄积,H2S减少免疫细胞和心血管细胞表面的腺苷A2A受体的表达,使动脉的血管舒张和淋巴细胞的免疫抑制作用下降,最终促进了缺血和炎症过程,从而加重CAD。HHcy患者的冠心病风险增加可能是腺苷能系统中H2S水平升高的结果,而Hcy升高的CAD患者与AS负荷较高相关[41]。

Werida等[42]研究表明,CAD患者中血浆Hcy浓度显著升高,并且发现在高Hcy水平的受试者中,CAD危险因素较正常水平Hcy患者更多,发生CAD风险的可能性显著增加,且在冠状动脉内皮细胞中形成的斑块更容易脱落,Hcy水平升高与冠状动脉狭窄密切相关。血清Hcy水平因冠心病的不同类型而异,并与冠状动脉狭窄的程度相关,因此,可用作早期检测和疾病评估的敏感指标[43-44]。

Markovi?-Boras等[45]研究发现Hcy是急性心力衰竭(acute heart failure,AHF)的危险因素之一,AHF组患者中HHcy的患病率显著较高,表明MI组中HHcy与心血管事件之间存在强相关性[46]。Psotka等[47]研究显示,AMI患者血清Hcy显著高于健康人水平,随着AMI病情的加重,血清Hcy水平明显上升。而在急性冠脉综合征(acute coronary syndrome,ACS)患者中,高Hcy水平的患者在长期随访中有较高的AHF复发风险[48]。Nedelcu等[46]研究结果支持血浆Hcy水平升高与年轻患者的首次AHF之间存在强相关性。因此,我们需要通过相关检查及时发现,尽早干预,而Hcy有望成为判断早期AHF的指标之一。

4 总结

Hcy水平升高可导致内皮细胞损伤、氧化应激、AS、心脏重构,从而增加心血管事件,如高血压、HF、冠心病,因此,任何年龄段的人群,不仅要控制吸烟、糖尿病、肥胖等危险因素,更应该将Hcy与上述因素放在同等位置去预防。

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(收稿日期:2023-09-11) (本文編辑:陈韵)

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