动脉粥样硬化作为一个重要的心血管疾病研究领域,世界医学界已对其进行了大量的探索和研究。期间因科技技术的局限性,对其认识停滞,甚至遭遇坎坷,但近些年伴随研究规模的快速发展,关于AS的研究成果也令人瞩目。本文通过搜索国内知网、万方,国外Pubmed等大型搜索网站有关动脉粥样硬化研究历史背景、观点及最新研究进展等相关文献资料,并进行整理汇总,梳理国内外研究,总结动脉粥样硬化最新研究进展,重点结合最新相关研究成果,希望能理清动脉粥样硬化各研究学说之间联系,为将来动脉粥样硬化研究方向提出一些建设性意见。
Atherosclerosis, as an important field of cardiovascular disease research, has been explored and studied by the world medical community for hundreds of years. During this period, due to the limi-tations of scientific and technological technology, the understanding of it is stagnant and even bumpy, but in recent years, with the rapid development of research scale, the research results on AS are also remarkable. In this paper, by searching the historical background, viewpoint and latest research progress of atherosclerosis research on large search websites such as domestic knowledge network, Wanfang and foreign Pubmed, and sorting out and summarizing the domestic and foreign research, summarizing the latest research progress of atherosclerosis, focusing on combining the latest relevant research results, hoping to sort out the relationship between the research theories of atherosclerosis and put forward some constructive opinions for the future research direction of atherosclerosis.
动脉粥样硬化学说,研究进展, Atherosclerosis Theory Research Progress摘要
Atherosclerosis Research: Origin, Viewpoint and Development Trend
Chen Li1, Rong Li2*, Li Li3
1Department of Geriatrics, Affiliated Hospital of Qinghai University, Xining Qinghai
2Department of General Practice, Affiliated Hospital of Qinghai University, Xining Qinghai
3Department of Neurology, The First People’s Hospital of Xianyang, Xianyang Shaanxi
Received: Apr. 27th, 2022; accepted: May 21st, 2022; published: May 31st, 2022
ABSTRACT
Atherosclerosis, as an important field of cardiovascular disease research, has been explored and studied by the world medical community for hundreds of years. During this period, due to the limitations of scientific and technological technology, the understanding of it is stagnant and even bumpy, but in recent years, with the rapid development of research scale, the research results on AS are also remarkable. In this paper, by searching the historical background, viewpoint and latest research progress of atherosclerosis research on large search websites such as domestic knowledge network, Wanfang and foreign Pubmed, and sorting out and summarizing the domestic and foreign research, summarizing the latest research progress of atherosclerosis, focusing on combining the latest relevant research results, hoping to sort out the relationship between the research theories of atherosclerosis and put forward some constructive opinions for the future research direction of atherosclerosis.
Keywords:Atherosclerosis Theory, Research Progress
中国古代就有“胸痹”记载,但中医文集中无“动脉粥样硬化”一词。对于AS病理解剖描述,中国最早记载,秦汉以前的《黄帝内经》及《后汉书王莽传》。而西方最早的记录始于1575年,意大利著名解剖学家Gabriel Fallopius的学生Volcher Coiter整理出版Fallopius生前的演讲和他的学生的笔记,其中写到Fallopius观察到他称之为退化成骨样的动脉病理学改变,表明AS钙化病变的存在,这是目前发现的关于AS描述最早的文献(Volcher Coiter. De Avium Sceletis et Praecipius Musculis (Nuremberg, 1575) [1]。1695年,Joseph Conrad Bruner报告在尸检中发现主动脉和其它大血管变硬的病变。1784年法国François Poulletier,首次从胆结石中发现胆固醇,但当时不清除该物质与AS关系如何。1799年CH Parry尸解时发现硬化或骨化的死者冠脉血管内出现一些沙砾样物质,并认为该物质是引起心绞痛的主要原因。之后随病理学发展,1904年,德国Marchand正式提出“atherosclerosis”这一定义;1913年,俄国Nikolai Anitschkow首次进行AS实验性研究,之后关于AS研究才逐渐发展起来。
2.2. 动脉粥样硬化概念的演变
2000多年前,古罗马学者Celsius创立了“粥瘤”(Atheroma)这个术语,但当时指的是脂肪瘤(Fatty Tumour)。1755年,粥瘤被Albrecht von Haller用来描述为动脉内膜观察到的退行性病变。1815年,Joseph Hodgson在提出炎症与AS相关的同时,创立了“atheromatosis”一词以描述脂肪性动脉退行性病变。1829年,法国外科医生和病理学家Jean Lobstein在他的著作《Traité d’Anatomie Pathologique》(1933年出版)中首次使用了术语“Arteriosclerosis”,即“动脉硬化”。1904年,德国Felix Jacob Marchand将存在脂肪沉积且血管硬化的病变命名为“atherosclerosis”。如今,AS和动脉硬化则是不同概念。动脉硬化包含AS、细小动脉硬化及动脉中膜硬化。
Ross R.等,1973年首次提出损伤反应学说,指出AS起始是各种危险因素造成的动脉内膜损伤,后来球囊导管内膜剥脱试验验证了这一说法。然而,1975年Silkworth等发现,饮食诱导的AS模型早期病变亦存在内膜损伤或血小板粘附。随着对EC认识不断深入,内皮细胞功能障碍(ECD)被引入AS研究,ECD是指多种因素(如NO生物利用度下降、血管氧化应激、炎症反应、血管老化及血流动力学等)作用于血管内皮细胞(VECs)导致分泌功能紊乱(如内皮–间质转化),最终打破血管稳态。ECD有利于oxLDL浸润至内皮下层,且分泌大量黏附因子招募白细胞和单核细胞至血管壁,引发局部炎症反应,进一步引起局部AS斑块形成,因此,ECD也被认为是AS早期病变特征。也有研究发现ECD不止参与AS早期病变,还参与整个AS的发展过程,其主要机制为:血管ECD发生后,在各种病理因素持续作用下,EC形态及结构改变,导致局部血管内皮结构不完整,之后通透性增加,再接下来随损伤持续进行,MCP-1及黏附分子开始异常表达,单核细胞等迁移及粘附于血管内皮,随后分化为巨噬细胞,巨噬细胞吞噬脂质后转为泡沫细胞,最终局部血管壁呈慢性炎症增生;或者在VECs表面产生并累积活性氧,致使eNOS表达下调,NO合成减少,随之局部血管发生OS;还可通过产生多种细胞因子与细胞膜表面受体结合,激活JAK/STAT通路,使SOS激活,活化的SOS再激活PI3K-AKT通路促进NF-κB、TNF-α表达,进而调节OS和炎症反应。且研究还发现内皮细胞激活或凋亡时会释放出内皮细胞微粒(EMPs),其可影响内皮功能、炎症反应、血管生成、金属基质蛋白酶(MMP)等参与AS形成。并且内皮细胞焦亡还可促进黏附因子的表达触发单核细胞黏附 [22];促进脂质斑块形成;参与内膜损伤及修复过程而影响AS发生发展。总的来说,VECs在AS起始和发展过程均有重要作用,除常规抗炎、抗氧化、增加NO生物利用度治疗AS外,近年来相关研究发现 [23] 血小板膜包覆的介孔硅纳米颗粒(PMSN),其有血小板细胞膜包裹在人工合成的纳米颗粒表面所形成,是一种继承血小板膜各种成分,如糖蛋白受体、细胞粘附分子等,从而具备靶向多种疾病位点的能力的一种新型治疗材料,该材料对损伤血管有特异性粘附作用,具备血小板膜蛋白长时间循环和主动靶向性特点,对各种因素引起的血管内膜损伤具有一定修复作用,可能成为未来AS预防及治疗的研究方向之一。
Vincent du Vigneaud于1933年首次分离出血浆同型半胱氨酸(Hcy)。1969年,美国Kilmer Mc Cully发现,两名患有高胱氨酸血症儿童均存在AS病理特征,由此得出血浆Hcy高可能是早期血管疾病潜在原因。且许多病例对照研究和荟萃分析的大量数据也支持高同型半胱氨酸血症与血管疾病(如:高血压、冠心病等)关联,因此AS同型半胱氨酸学说开始日益流行起来。在近现代研究中人们逐渐认识到Hcy引起AS的机制主要包括 [30]:引起脂质代谢紊乱、促进血管EC损伤和凋亡、抑制纤溶、促进血小板聚集、激活炎症因子、引起脂质蓄积、促进VSMC增殖、造成NO通路障碍(抑制NO的生成)、引起OS反应、引起免疫反应等,还可通过改变SAM/SAH的动态平衡,导致DNA甲基化或高甲基化,通过表观遗传机制影响AS疾病的进展。此外,高水平的同型半胱氨酸可导致雌激素受体-α (ER-a)基因启动子区的高甲基化,而ER-α被认为是调节对EC和SMC有益雌激素作用的人类动脉粥样硬化保护基因 [31]。这些机制彼此相互联系、作用,从而导致AS发生发展。虽然Hcy的水平受营养供应水平的影响,如一碳单位供体营养叶酸,但目前尚无明确证据表明高同型半胱氨酸血症的治疗改变了甲基化过程,并对CHD有确切的疗效。
3.12. 精氨酸学说
L-精氨酸(L-Arg)是血管EC合成NO的前体,NO生物学作用包括:扩张血管,抑制白细胞与内皮细胞粘附、抑制PLC聚集粘附,抑制VSMC增殖、降低LDL合成、抑制LDL氧化、促进HDL合成、调节凝血/纤溶功能等。而NO的发现与硝酸酯类药物的研究密不可分。1847年,意大利Ascanio Sobrero发现治疗心绞痛的特效药物硝酸甘油,当时不了解该药治疗心绞痛的具体原因,后来这种易爆且非常不稳定的物质又被瑞典Alfred Bernhard Nobel研制成安全炸药。1980年Furchgott和Zawadski首次发现,被它们命名为内皮细胞衍生舒张因子(EDRF)的物质对血管有舒张反应作用。而Palmer于1987年则证实EDRF即NO,且后来证实硝酸酯药物也主要通过此物质起作用。1988年Richard MJ等人证明,L-Arg是血管EC合成NO的前体。但硝酸甘油缓解心绞痛机制,直到一百多年后,在医学家Robert F.Furchgott等人的共同努力下才揭开,并获得1998年诺贝尔医学奖。该机制具体内容是硝酸甘油在体内经代谢,代谢为NO,而NO则在舒张血管作用中起“信使”作用,从而改善血液循环。近现代大量研究还发现,NO也是体内重要的效应分子及免疫调节分子,且NO利用度降低、合成减少或其信号通路功能紊乱等均可影响AS发生发展。
李 晨,李 蓉,李 立. 动脉粥样硬化研究:缘起、观点及发展趋势Atherosclerosis Research: Origin, Viewpoint and Development Trend[J]. 临床医学进展, 2022, 12(05): 4934-4950. https://doi.org/10.12677/ACM.2022.125716
参考文献References杨永宗, 刘录山. 中国动脉粥样硬化纪事(十二) [J]. 中国动脉硬化杂志, 2016, 24(12): 1292-1296.Ali, M., Girgis, S., Hassan, A., et al. (2018) Inflammation and Coronary Artery Disease: From Pathophysiology to Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Coronary Artery Disease, 29, 429-437.
<br>https://doi.org/10.1097/MCA.0000000000000625Raman, P. and Khanal, S. (2021) Leptin in Atherosclerosis: Focus on Macrophages, Endothelial and Smooth Muscle Cells. International Journal of Molecular Sciences, 22, 5446. <br>https://doi.org/10.3390/ijms22115446Naryzhnaya, N.V., Koshelskaya, O.A., Kologrivova, I.V., et al. (2021) Hypertrophy and Insulin Resistance of Epicardial Adipose Tissue Adipocytes: Association with the Coronary Artery Disease Severity. Biomedicines, 9, 64.
<br>https://doi.org/10.3390/biomedicines9010064Christensen, R.H., Wedell-Neergaard, A.S., Lehrskov, L.L., et al. (2019) Effect of Aerobic and Resistance Exercise on Cardiac Adipose Tissues: Secondary Analyses from a Random-ized Clinical Trial. JAMA Cardiology, 4, 778-787.
<br>https://doi.org/10.1001/jamacardio.2019.2074Galvez, R., Portano, J., Cortes, R.T., et al. (2020) Reduction of Epicardial Adipose Tissue Thickness with PCSK9 Inhibitors. European Heart Journal, 41, ehaa946.3008. <br>https://doi.org/10.1093/ehjci/ehaa946.3008Parisi, V., Petraglia, L., D’Esposito, V., et al. (2019) Statin Thera-py Modulates Thickness and Inflammatory Profile of Human Epicardial Adipose Tissue. International Journal of Cardi-ology, 274, 326-330.
<br>https://doi.org/10.1016/j.ijcard.2018.06.106Ziyrek, M., Kahraman, S., Ozdemir, E., et al. (2019) Metformin Monotherapy Significantly Decreases Epicardial Adipose Tissue Thickness in Newly Diagnosed Type 2 Diabetes Pa-tients. Revista Portuguesa de Cardiologia, 38, 419-423.
<br>https://doi.org/10.1016/j.repc.2018.08.010Salim, H.M., Fukuda, D., Higashikuni, Y., et al. (2017) Ten-eligliptin, a Dipeptidyl Peptidase-4 Inhibitor, Attenuated Pro-Inflammatory Phenotype of Perivascular Adipose Tissue and Inhibited Atherogenesis in Normoglycemic Apolipoprotein-E-Deficient Mice. Vascular Pharmacology, 96-98, 19-25. <br>https://doi.org/10.1016/j.vph.2017.03.003Nogueira, J.P. (2021) Effect of SGLT2-Inhibitors on Epi-cardial Adipose Tissue: A Meta-Analysis. Cells, 10, 2150.
<br>https://doi.org/10.3390/cells10082150Tsjoa, B., Atlfc, D., Avb, A., et al. (2021) Colchicine in Patients with Chronic Coronary Disease in Relation to Prior Acute Coronary Syndrome. Journal of the American College of Cardiol-ogy, 78, 859-866.
<br>https://doi.org/10.1016/j.jacc.2021.06.037Allen, N., Barrett, T.J., Guo, Y., et al. (2019) Circulating Mono-cyte-Platelet Aggregates Are a Robust Marker of Platelet Activity in Cardiovascular Disease. Atherosclerosis, 282, 11-18.
<br>https://doi.org/10.1016/j.atherosclerosis.2018.12.029Marchio, P., Guerra-Ojeda, S., Vila, J.M., et al. (2019) Targeting Early Atherosclerosis: A Focus on Oxidative Stress and Inflammation. Oxidative Medicine and Cellular Lon-gevity, 2019, Article ID: 8563845.
<br>https://doi.org/10.1155/2019/8563845Kuravi, S.J., Harrison, P., Rainger, G.E., et al. (2019) Ability of Plate-let-Derived Extracellular Vesicles to Promote Neutrophil-Endothelial Cell Interactions. Inflammation, 42, 290-305. <br>https://doi.org/10.1007/s10753-018-0893-5Hartley, B.A., Fmedsci, D. and Rkmc, F. (2019) Oxidized LDL and Anti-Oxidized LDL Antibodies in Atherosclerosis—Novel Insights and Future Directions in Diagnosis and Therapy. Trends in Cardiovascular Medicine, 29, 22-26.
<br>https://doi.org/10.1016/j.tcm.2018.05.010Morton, A.M., Koch, M., Mendivil, C.O., et al. (2018) Apolipo-proteins E and CIII Interact to Regulate HDL Metabolism and Coronary Heart Disease Risk. JCI Insight, 3, e98045. <br>https://doi.org/10.1172/jci.insight.98045Lu, Y., Cui, X., Zhang, L., et al. (2022) The Functional Role of Lip-oproteins in Atherosclerosis: Novel Directions for Diagnosis and Targeting Therapy. Aging and Disease, 13, 491-520.Shu, H., Peng, Y., Hang, W., et al. (2022) Emerging Roles of Ceramide in Cardiovascular Diseases. Ag-ing and Disease, 13, 232-245. <br>https://doi.org/10.14336/AD.2021.0710Amirfakhryan, H. (2020) Vaccination against Atherosclerosis: An Overview. Hellenic Journal of Cardiology, 61, 78-91.
<br>https://doi.org/10.1016/j.hjc.2019.07.003Higashi, Y., Noma, K., Yoshizumi, M., et al. (2009) Endothelial Function and Oxidative Stress in Cardiovascular Diseases. Circulation Journal, 73, 411-418. <br>https://doi.org/10.1253/circj.CJ-08-1102蒋琬姿, 张丽雯, 贺彩红, 阮梅花, 季勇, 于建荣, 等. 家族性高胆固醇血症研究进展[J]. 遗传, 2021, 43(11): 1011-1040.Chen, L., Zhou, Z., Hu, C., et al. (2022) Platelet Mem-brane-Coated Nanocarriers Targeting Plaques to Deliver Anti-CD47 Antibody for Atherosclerotic Therapy. Research, 2022, Article ID: 9845459.
<br>https://doi.org/10.34133/2022/9845459Yin, J., Xia, W., Wu, M., et al. (2019) Inhibition of Mitochondrial Complex I Activity Attenuates Neointimal Hyperplasia by Inhibiting Smooth Muscle Cell Proliferation and Migration. Chemico-Biological Interactions, 304, 73-82.
<br>https://doi.org/10.1016/j.cbi.2019.03.002Zullo, A., Guida, R., Sciarrillo, R., et al. (2022) Redox Homeostasis in Cardiovascular Disease: The Role of Mitochondrial Sirtuins. Frontiers in Endocrinology, 13, Article ID: 858330. <br>https://doi.org/10.3389/fendo.2022.858330Razeghian-Jahromi, I., Karimi, A.A., Razmkhah, M., et al. (2022) Immune System and Atherosclerosis: Hostile or Friendly Relationship. International Journal of Immunopathology and Pharmacology, 36, Article ID: 1190312284.
<br>https://doi.org/10.1177/03946320221092188Yoo, J.Y., Sniffen, S., McGill, P.K., et al. (2022) Gut Dysbiosis and Immune System in Atherosclerotic Cardiovascular Disease (ACVD). Microorganisms, 10, Article No. 108. <br>https://doi.org/10.3390/microorganisms10010108He, L., Zhang, C.L., Chen, Q., et al. (2022) Endothelial Shear Stress Signal Transduction and Atherogenesis: From Mechanisms to Therapeutics. Pharmacology & Therapeutics, 235, Article ID: 108152.
<br>https://doi.org/10.1016/j.pharmthera.2022.108152Tao, J., Cao, X., Yu, B., et al. (2022) Vascular Stem/Progenitor Cells in Vessel Injury and Repair. Frontiers in Cardiovascular Medicine, 9, Article ID: 845070. <br>https://doi.org/10.3389/fcvm.2022.845070Guieu, R., Ruf, J. and Mottola, G. (2022) Hyperhomocysteinemia and Cardiovascular Diseases. Annales de Biologie Clinique, 80, 7-14. <br>https://doi.org/10.1684/abc.2021.1694Dai, Y., Chen, D. and Xu, T. (2022) DNA Methylation Aberrant in Atherosclerosis. Frontiers in Pharmacology, 13, Article ID: 815977. <br>https://doi.org/10.3389/fphar.2022.815977浦冬青, 刘政, 周超, 梁佳玮, 郝清智. 近10年动脉粥样硬化发病机制研究热点的可视化分析[J]. 世界科学技术-中医药现代化, 2021, 23(7): 2276-2284.Yu, N., Wang, R., Liu, B., et al. (2022) Bibliometric and Visual Analysis on Metabolomics in Coronary Artery Disease Research. Fron-tiers in Cardiovascular Medicine, 9, Article ID: 804463. <br>https://doi.org/10.3389/fcvm.2022.804463