药学学报

Clinical study	Sample (number)	Method	Finding	Reference
Angioplasty, PPCI	Plaque (12)	LC-MS/MS	The specific OxPL and OxCE were presented in plaque, and 1-palmitoyl-2-[9-oxo-nonanoyl] PC, represented a major phosphatidylcholine-OxPL molecule quantitated within plaque material	[22]
CAD	Plasma (3384)	UHPLC-MS	Cer (d18∶1/16∶0), Cer (d18∶1/18∶0), Cer (d18∶1/24∶0), and Cer (d18∶1/24∶1) are high-risk ceramides of CAD, and the Cer (d18∶1/16∶0)/Cer (d18∶1/24∶0) ratio is a lipid marker cardiovascular death	[28]
Heart failure	Serum (433)	LC-MS	Increased circulating concentration ceramides 16∶0 and 18∶0 are associated with HFpEF (heart failure with preserved ejection fraction)	[29]
CAD	Plasma (2217)	LC-MS	The specific very-long-chain fatty ceramides (C24∶0 and C22∶0) were associated with a reduced incidence of coronary heart disease and all-cause mortality. The SNPs of SPTLC3 (serine palmitoyltransferase long chain base subunit 3) were associated with plasma C22∶0 and C24∶0 ceramide concentrations	[30]
Diabetes, CVD, HF	Plasma (4612)	LC-MS	Higher levels of Cer-16 and SM-16 were associated with a higher risk of mortality, while higher levels of Cer-22, Cer-24, SM-20, SM-22, and SM-24 were associated with a lower risk of mortality	[31]
	Serum (64)	LC-MS	Patients with various stages of HF had increased circulating levels of ceramides, as well as elevated cardiac levels of ceramides, particularly long- and very long-chain species. Both mice and humans with HF had increased levels of SPTLC2	[32]
HF	Heart tissure (31)	LC-MS/MS	Certain ceramide species, such as Cer d18∶1/16∶0, Cer d18∶1/18∶1, and Cer d18∶1/24∶1 SPTLC1 and SPTLC2 expression were significantly increased in human ICM heart tissue samples	[33]
Stable CAD, AMI	Plasma (35)	LC-MS	Reduced levels of four PC plasmalogens (PC33∶1, PC33∶2, PC33∶3 and PC35∶3) were identified as a putatively novel lipid signature for CAD and AMI	[34]
ACS, CSA	Plasma (130)	LC-MS/MS	Compared with stable coronary artery disease, ACS plasma was lower in phospholipids including lyso species and plasmalogens, with the majority of lipid species differing in abundance located within high-density lipoprotein	[35]
Hypertriglyceridemia	Plasma (111)	UPLC-LTQ-Orbitrap MS	Compared with control group, lysoPCs, amides, and cis-4-octenedioic acid among non-diabetic and non-obese individuals with HTG had alterations	[36]
CHD, CHD+CBD, MI	Plasma (49)	LC-MS	The oxidation products of LA-CE and AA-CE in plasma of patients with MI increased, compared to control and other CVD groups. Among these oxidation products, ch-13(c, t)-HODE is one of the major components that are significantly elevated in plasma of MI patients	[37]
SA, MI	Plasma (28)	UHPLC-QTOF/MS	Oxidized PL and their hydrolyzed fatty acids were closely associated with CHD. These oxidative stress-induced LPO products overwhelmed the enzymatic products of arachidonic acid and linoleic acid, especially in plasma from MI patients. lysoPC (20∶0), lysoPC (20∶1), lysoPC (20∶2), lysoPC (20∶5), lysoPC (22∶5), lysoPE (18∶3), and glycerophosphocholine were differential metabolites in CHDs. Besides, lysoPA (18∶2) (one of the main lysoPA species) and lysoPS (20∶4) were increased in MI patients compared to healthy controls or SA patients	[38]
Autopsy or CAD	Plaque (4+4)	LC/ESI-MS/MS	A novel series of oxidation products containing the cyclopentenone moiety, termed deoxy-A2/J2-IsoP-PCs in vivo, which formed as intact phospholipids via free radical-catalyzed peroxidation of PAPC	[39]
CHD	Plasma (30)	LC/ESI-MS/MS	The levels of the total amounts of deoxy-A2/J2-IsoP-PC and deoxy-A2/J2-IsoPs were decreased in the plasma of CHD patients compared with the healthy subjects, consistent with a protective role of these compounds in cardiovascular diseases	[39]

Clinical study	Sample (number)	Method	Finding	Reference
Angioplasty, PPCI	Plaque (12)	LC-MS/MS	The specific OxPL and OxCE were presented in plaque, and 1-palmitoyl-2-[9-oxo-nonanoyl] PC, represented a major phosphatidylcholine-OxPL molecule quantitated within plaque material	[22]
CAD	Plasma (3384)	UHPLC-MS	Cer (d18∶1/16∶0), Cer (d18∶1/18∶0), Cer (d18∶1/24∶0), and Cer (d18∶1/24∶1) are high-risk ceramides of CAD, and the Cer (d18∶1/16∶0)/Cer (d18∶1/24∶0) ratio is a lipid marker cardiovascular death	[28]
Heart failure	Serum (433)	LC-MS	Increased circulating concentration ceramides 16∶0 and 18∶0 are associated with HFpEF (heart failure with preserved ejection fraction)	[29]
CAD	Plasma (2217)	LC-MS	The specific very-long-chain fatty ceramides (C24∶0 and C22∶0) were associated with a reduced incidence of coronary heart disease and all-cause mortality. The SNPs of SPTLC3 (serine palmitoyltransferase long chain base subunit 3) were associated with plasma C22∶0 and C24∶0 ceramide concentrations	[30]
Diabetes, CVD, HF	Plasma (4612)	LC-MS	Higher levels of Cer-16 and SM-16 were associated with a higher risk of mortality, while higher levels of Cer-22, Cer-24, SM-20, SM-22, and SM-24 were associated with a lower risk of mortality	[31]
	Serum (64)	LC-MS	Patients with various stages of HF had increased circulating levels of ceramides, as well as elevated cardiac levels of ceramides, particularly long- and very long-chain species. Both mice and humans with HF had increased levels of SPTLC2	[32]
HF	Heart tissure (31)	LC-MS/MS	Certain ceramide species, such as Cer d18∶1/16∶0, Cer d18∶1/18∶1, and Cer d18∶1/24∶1 SPTLC1 and SPTLC2 expression were significantly increased in human ICM heart tissue samples	[33]
Stable CAD, AMI	Plasma (35)	LC-MS	Reduced levels of four PC plasmalogens (PC33∶1, PC33∶2, PC33∶3 and PC35∶3) were identified as a putatively novel lipid signature for CAD and AMI	[34]
ACS, CSA	Plasma (130)	LC-MS/MS	Compared with stable coronary artery disease, ACS plasma was lower in phospholipids including lyso species and plasmalogens, with the majority of lipid species differing in abundance located within high-density lipoprotein	[35]
Hypertriglyceridemia	Plasma (111)	UPLC-LTQ-Orbitrap MS	Compared with control group, lysoPCs, amides, and cis-4-octenedioic acid among non-diabetic and non-obese individuals with HTG had alterations	[36]
CHD, CHD+CBD, MI	Plasma (49)	LC-MS	The oxidation products of LA-CE and AA-CE in plasma of patients with MI increased, compared to control and other CVD groups. Among these oxidation products, ch-13(c, t)-HODE is one of the major components that are significantly elevated in plasma of MI patients	[37]
SA, MI	Plasma (28)	UHPLC-QTOF/MS	Oxidized PL and their hydrolyzed fatty acids were closely associated with CHD. These oxidative stress-induced LPO products overwhelmed the enzymatic products of arachidonic acid and linoleic acid, especially in plasma from MI patients. lysoPC (20∶0), lysoPC (20∶1), lysoPC (20∶2), lysoPC (20∶5), lysoPC (22∶5), lysoPE (18∶3), and glycerophosphocholine were differential metabolites in CHDs. Besides, lysoPA (18∶2) (one of the main lysoPA species) and lysoPS (20∶4) were increased in MI patients compared to healthy controls or SA patients	[38]
Autopsy or CAD	Plaque (4+4)	LC/ESI-MS/MS	A novel series of oxidation products containing the cyclopentenone moiety, termed deoxy-A2/J2-IsoP-PCs in vivo, which formed as intact phospholipids via free radical-catalyzed peroxidation of PAPC	[39]
CHD	Plasma (30)	LC/ESI-MS/MS	The levels of the total amounts of deoxy-A2/J2-IsoP-PC and deoxy-A2/J2-IsoPs were decreased in the plasma of CHD patients compared with the healthy subjects, consistent with a protective role of these compounds in cardiovascular diseases	[39]

基于脂质组学技术发现冠心病的脂质标志物和治疗靶点

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杨冠林 ¹^,³^,^# , 翟琼 ¹^,^# , 董馨 ² , 布仁 ² , 薛培凤 ² , 赵芳新 ¹ , 陆景坤 ¹^,^*

药学学报 | 综述 2022,57(7): 2003-2011

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药学学报 | 综述 2022, 57(7): 2003-2011

基于脂质组学技术发现冠心病的脂质标志物和治疗靶点

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杨冠林¹^,³^,^#, 翟琼¹^,^#, 董馨², 布仁², 薛培凤², 赵芳新¹, 陆景坤¹^,^*

作者信息

1.内蒙古医科大学基础医学院, 内蒙古自治区呼和浩特 010010

2.内蒙古医科大学药学院, 内蒙古自治区呼和浩特 010010

3.枣庄市肿瘤医院, 山东枣庄 277000

通讯作者:

*陆景坤, E-mail: 360569392@qq.com

Lipid markers and targets of coronary artery disease based on lipidomics

Guan-lin YANG¹^,³, Qiong ZHAI¹, Xin DONG², Ren BU², Pei-feng XUE², Fang-xin ZHAO¹, Jing-kun LU¹^,^*

Affiliations

1. School of Basic Medicine, Inner Mongolia Medical University, Hohhot 010010, China

2. College of Pharmacy, Inner Mongolia Medical University, Hohhot 010010, China

3. Zaozhuang Cancer Hospital, Zaozhuang 277000, China

出版时间: 2022-07-12 doi: 10.16438/j.0513-4870.2022-0280

文章导航

摘要

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冠心病是全球第一的死亡原因, 其主要特征是冠状动脉粥样硬化使管腔狭窄或闭塞导致心肌缺血、缺氧或坏死而引发的心脏病, 冠心病与脂质调节异常、慢性炎症、内皮功能障碍等密切相关。目前用于诊断冠心病的心肌酶和高、低密度脂蛋白等只能部分解释冠心病的风险。尚不能有效地检测冠心病患者早期的高危因素, 迫切需要新的技术发现与冠心病密切相关的疾病标志物。脂质分子是心肌细胞结构重要组成部分, 在心脏功能方面扮演重要角色。脂质组学是高通量研究脂质组成的一门新兴学科。近年脂质组学研究显示, 特定种类的脂类, 如神经酰胺、鞘氨醇、溶血磷脂酸、氧化脂质等, 与冠心病的临床分型及特征相关。此外动物模型中心脏、脂肪、肝脏等相关组织样本脂质组学研究成果也为脂质生物标志物提供了新的信息, 脂质组学技术正越来越多地被用于评估冠心病的风险等相关研究。本文对利用脂质组学技术探究冠心病脂质小分子标志物以及相关治疗靶点、药物研发策略进行综述。

关键词

脂质分子 / 脂质组学 / 冠心病 / 疾病标志物 / 治疗靶点

Abstract

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Coronary artery disease is the leading cause of death worldwide, the coronary artery stenosis or occlusion caused by atherosclerosis leads to myocardial ischemia, hypoxia, or necrosis, that is main histopathological features of coronary artery disease. Atherosclerosis relates closely to abnormal lipid regulation, chronic inflammation, and endothelial dysfunction. Cardiac enzymes and high, low-density lipoprotein are currently used to diagnose a variety of coronary artery diseases, but the evidence is inadequate. Thus, new cardioprotective therapies are required to explore sensitive molecular markers for the prediction of cardiovascular events. Lipids have an important role in maintaining the myocardial cell structure as well as cardiac function. Lipidomics is a newly emerged discipline that studies lipids on a large scale. Recent advancements in lipidomics on coronary artery disease have shown that certain lipids, such as ceramide, sphingosine, lysophosphatidic acid, oxidized lipids, and so on, are associated with the clinical classification and characteristics of coronary artery disease. In addition, recent studies of lipid profiles of the cardiac, fat, liver, and other tissue samples in animal models also have provided a novel viewpoint. Given the increasing application of lipidomics techniques for coronary artery disease, we provide a review of lipidomics technology, sensitive lipid markers, recent studies of therapeutic targets, and drug discovery for coronary artery disease.

Key words

lipid molecule / lipidomics / coronary artery disease / sensitive lipid marker / therapeutic target

引用本文

杨冠林, 翟琼, 董馨, 布仁, 薛培凤, 赵芳新, 陆景坤. 基于脂质组学技术发现冠心病的脂质标志物和治疗靶点. 药学学报, 2022 , 57 (7) : 2003 -2011 . DOI: 10.16438/j.0513-4870.2022-0280

Guan-lin YANG, Qiong ZHAI, Xin DONG, Ren BU, Pei-feng XUE, Fang-xin ZHAO, Jing-kun LU. Lipid markers and targets of coronary artery disease based on lipidomics[J]. Acta Pharmaceutica Sinica, 2022 , 57 (7) : 2003 -2011 . DOI: 10.16438/j.0513-4870.2022-0280

正文

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冠心病是全球第一位的死亡原因, 我国2018年统计显示农村、城市冠心病分别占死因的46.66%和43.81%^[1]。冠心病多发于中老年人群, 男性多于女性。临床上将冠心病分为慢性心肌缺血综合征和急性冠脉综合征(acute coronary syndrome, ACS), 前者又细分为隐匿型冠心病、慢性稳定型心绞痛及缺血性心肌病等; 急性冠脉综合征包括ST段抬高型心肌梗死、非ST段抬高型心肌梗死及不稳定型心绞痛。冠状动脉粥样硬化(atherosclerosis, AS) 是冠心病的主要潜在因素, 可同时或分别累及各主要的冠状动脉, 病变的狭窄程度、部位决定了缺血症状和预后。冠心病的主要风险因素包括高血压、糖尿病、血脂异常、肥胖和超重、吸烟等^[2]。目前, 冠心病急性发作住院治疗多采用溶栓、直接经皮冠状动脉介入治疗^[3]; 治疗药物包括受体阻滞剂、硝酸酯类、他汀类、代谢改善类、抗血栓类药物及血管紧张素转化酶抑制剂^{[2, 4]}。

AS进程主要包括血管壁脂质和胆固醇蓄积、泡沫细胞形成、慢性炎症、内皮功能障碍、血管平滑肌细胞表型转化和迁移增殖、细胞死亡以及血栓形成等^[5]。诊断主要依据心电图、血管造影、肌钙蛋白、肌酸激酶、高/低密度脂蛋白胆固醇等, 以及胸痛等临床表现, 然而这些只能部分解释心血管疾病的风险, 尚不能有效地检测冠心病患者早期的高危因素, 迫切需要新的技术寻找与冠心病的预防、诊断和预后相关的生物标志物。随着近年来质谱的快速发展, 脂质组学成为发现冠心病生物标志物的有效手段, 循环脂质越来越多地被纳入风险模型中来预测心血管事件^{[6, 7]}。与脂质代谢相关的酶有可能成为有吸引力的治疗靶点, 将有助于开发新的治疗方法, 指导新药的研发。因此, 本文对脂质、脂质组学、与冠心病密切相关的脂质分子及其相应的治疗靶点进行综述。

1 脂质的种类及功能

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脂质既是细胞、亚细胞膜、脂蛋白的组成部分, 能量储存成分, 也作为细胞因子或信号分子参与调节细胞信号过程。脂类分子基本组成包括主链、头基和脂肪链, 含有极性/离子头基团(如磷脂和鞘脂) 和非极性脂肪链, 是一类两亲性分子, 按结构分为鞘脂类(sphingolipids, SP)、甘油脂类(slycerolipids, GL)、脂肪酰类(fattyacyls, FA)、甘油磷脂类(glycerophospholipids, GP)、甾醇脂类(sterol lipids, ST)、糖脂类(saccharolipids, SL) 等, 该部分针对近年来关注较多且与冠心病密切相关的鞘脂亚类、甘油磷脂亚类、氧化脂质及其重点脂质分子的结构和功能做简单介绍。

1.1 鞘脂类

鞘脂是细胞膜的主要结构成分。其基本结构是由氨基酸与酰基辅酶A (acyl-CoA) 缩合生成氨基醇或鞘基, 鞘基随后通过酰化、磷酸化、糖基化和/或添加多个头基或其他官能团进行修饰形成鞘氨醇(sphingosine, SPH)、鞘磷脂(sphingomyelin, SM)、神经酰胺(ceramide, Cer)、鞘糖脂(glycosphingolipid, GSL) 等数百种SP亚类, 参与调节细胞分裂、衰老、迁移、分化、凋亡、自噬、营养摄取、代谢和蛋白质合成等。其中研究较多的是Cer和鞘氨醇磷酸酯(sphingosine-1-phosphate, S1P)。

Cer是一种多样化的鞘脂亚类, 由一个长链碱基和一个酰胺连接的脂肪酰基链组成, 有0或1个双键, 根据酰基链的长度可分为中等(12-14碳)、长(16-20碳)、很长(22-26碳) 和超长链(> 26碳) Cer。其生物合成始于内质网, 包括新生途径、回收途径和鞘磷脂酶途径^[8]。从头合成的限速酶是丝氨酸棕榈酰转移酶(新生途径), 主要通过囊泡转运或Cer转运蛋白, 运送到高尔基体, 进一步与糖或磷酸胆碱结合为GSL或SM等复合鞘脂。正常生理情况下, 复合鞘脂可经鞘磷脂酶催化分解生成Cer, 为鞘磷脂酶途径。Cer被神经酰胺酶水解, 产生SPH, SPH又可重新整合成Cer (回收途径) 或被鞘氨醇激酶(sphingosine kinase, SphK1和SphK2) 磷酸化产生S1P, S1P裂解酶(S1P lyase, SPL) 将S1P分解为非鞘脂类成分脂肪醛和磷酸乙醇胺后从细胞鞘脂池中排出; SPL是鞘脂代谢途径的唯一出口, 是总细胞鞘脂水平的主要调节因子^[9]。Cer在调节细胞鞘脂稳态中起重要作用; 小鼠和斑马鱼实验研究显示维持适当浓度的S1P是心脏瓣膜前体正常发育的保障^[10]; SPH在Cer和S1P合成中起桥接作用, 但其生理作用似乎有限^[11]; GSL也被认为可能是致动脉粥样硬化的脂质, 但是抑制GSL合成本身是否具有抗动脉粥样硬化作用仍存在争议^[12]。

1.2 甘油磷脂类

细胞膜的生物物理性质取决于甘油磷脂组成。GP因为甘油的羟基被酯化的个数分为甘油磷脂和溶血甘油磷脂(lyso-glycerophospholipids, LysoGP), GP具有一个共同的甘油基础结构, 在甘油主链的sn-3位置有一个含磷酸盐的头基, 两个疏水脂肪链连接在sn-1和sn-2位置。GP主要包括甘油磷酸胆碱(glycerophosphocholines, PC)、甘油磷酸乙醇胺(glycerophosphoethanolamines, PE)、甘油磷酸丝氨酸(glycerophosphoserines, PS)、磷脂酰甘油(glycerophosphoglycerol, PG)、磷脂酰肌醇(phosphatidylinositoles, PI)、心磷脂(cardiolipin, CL)、溶血磷脂类(lysophospholipids)、磷脂酸(phosphatidic acid, PA) 等。PC和PE是细胞膜和脂蛋白中主要GP, 占总GP的一半以上, PS参与细胞融合、吞噬和凋亡, PI参与囊泡运输, CL是细胞内线粒体膜的主要组成部分^[13], PA是最简单的GP, 是其他GP生物合成的关键中间体。GP类研究较多的有PC亚类的1-棕榈酰-亚油基-sn-丙三基-磷脂酰胆碱(1-palmitoyl-linoleoyl-sn-glycero-3-phosphatidylcholine, PLPC)、磷脂1-棕榈酰-2-花生四烯酰-sn-甘油-3-磷胆碱(phospholipid 1-pal mitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine, PAPC)、缩醛磷脂(plasmalogen)、CL和溶血甘油磷脂亚类的溶血磷脂酸(lysophosphatidic acid, LPA)。

PLPC和PAPC是含有多不饱和脂肪酸(polyunsatu-rated fatty acid, PUFA) 的两类化合物, 前者是脂蛋白颗粒中GP之一, 后者是细胞膜、肺表面活性物质和循环脂蛋白的组成成分。因为含有PUFA, 易受活性氧攻击, 发生非酶促氧化, 参与机体的病理生理过程^[6]。

缩醛磷脂类是PC的亚类, 包括磷脂酰胆碱缩醛磷脂和磷脂酰乙醇胺缩醛磷脂等, 其特征是一个顺式乙烯醚键将一个烷基链连接到甘油主链的sn-1位置^[14]。研究显示缩醛磷脂参与细胞内胆固醇运输和高密度脂蛋白介导的胆固醇外排, 可以防止磷脂双层中胆固醇的氧化, 有潜在的动脉粥样硬化保护作用^{[14, 15]}。

溶血甘油磷脂亚类(LysoGP) 是以单甘油酯为母核, 在sn-1位置有一个长疏水碳链, sn-3有一个含磷酸盐头基的一类化合物, 如溶血磷脂酰胆碱(lysophosphatidyl choline, lysoPC)、溶血磷脂酰丝氨酸(lysophosphatidylserine, lysoPS)、溶血磷脂酰乙醇胺(lysophosphatidylethanolamine, lysoPE) 和溶血磷脂酰肌醇(lysophosphatidyl inositol, lysoPI)。LysoGP在细胞中浓度很低, 是细胞中其他脂类生物合成的中间前体, 但其在血浆、间质液中含量丰富。在这些细胞外环境中, LysoGP能与蛋白质载体结合, 在高浓度时可能对细胞有毒, 因为它们破坏膜结构并导致细胞裂解。lysoPC是血液中最丰富的LysoGP, 其次是lysoPE和LPA^[11]。lysoPC被认为是神经细胞膜生物合成的重要来源, 可能是大脑发育和生长过程中脂肪酸传递的关键途径^[16]。

LPA是一类甘油1-磷酸衍生物, autotaxin (ATX) 是LPA产生的关键酶, 能将一系列LysoGP, 转化为LPA和相应的头基。在循环系统中, LPA的主要的亚型有16∶0、18∶1、18∶2和20∶4。LPA的受体分6个亚型, 与多种生理效应有关^[17]。目前已知的LPA信号转导途径有4种: ①经典G蛋白介导; ② β-抑制素介导; ③溶血磷脂酸受体转激活蛋白酪氨酸激酶受体或丝氨酸/苏氨酸激酶受体介导; ④通过过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptor, PPARγ) 传递LPA信号。在循环系统中, 血小板是LPA的主要来源之一, LPA反过来调节血小板形状、聚集、血小板-单核细胞聚集和纤维连接蛋白基质组装, 这些作用可导致血栓形成; 同时, 在ox-LDL和AS斑块的脂质中, LPA是主要的功能性脂质分子^{[18, 19]}。LPA的失活目前认为是由细胞表面的脂质磷酸酶家族介导的, 其中, LPP3可作为LPA信号转导的负调控因子, 将LPA水解失活^[18]。

CL亚类具有磷脂酰甘油二聚体结构, 其中一个甘油被两个PA酯化^[13]。CL是线粒体内膜的主要磷脂, 在心脏的能量代谢中起着重要的作用。四亚油酸是成熟心脏中主要的CL形式。CL参与许多与线粒体膜相关的基本功能, 包括线粒体的形态、代谢和呼吸。Barth综合征等遗传疾病都影响CL生物合成, 线粒体CL缺乏导致细胞凋亡和线粒体自噬; 缺血/再灌注损伤和心力衰竭时CL会显著降低^[20]。

1.3 氧化脂质

亚油酸(C18∶2ω6) 和花生四烯酸(C20∶4ω6) 是脂质结构中两种主要的PUFA。细胞膜和脂蛋白中的PUFAs的磷脂(phospholipids, PLs) 和胆固醇酯(cholesteryl ester, CEs) 易发生氧化, 包括正常生理条件下的酶促氧化和病理条件下的非酶促氧化。

正常生理条件下, 含有PUFA的脂质被环氧合酶(cyclooxygenase, COX)、脂氧合酶(lipoxygenase, LOX) 和细胞色素P450s催化发生酶促氧化, 产生的生物活性脂质介质前列腺素、血栓烷、前列环素、白三烯、消退素等广泛参与心血管系统的生理病理过程。此外, 含有PUFAs的脂质还容易受活性氧攻击, 导致非酶促氧化, 即脂质过氧化(lipid peroxidation, LPO), LPO产物, 如氧化磷脂(oxidized phospholipids, OxPL) 和氧化胆固醇酯(oxidized cholesterol ester, OxCE) 在局部或系统的产生和积累与一些炎症性疾病的病因和进展有关^{[6, 21]}。

OxPL负责维持免疫细胞和非免疫细胞的炎症反应, 例如, OxPL在巨噬细胞和树突状细胞中调节细胞代谢和促炎信号, 并改变这些细胞的激活和极化; 此外, OxPL也在调节血小板功能和血栓形成中发挥重要作用^[22]。

相对于PLs, CEs具有惰性, 是细胞内的“储存物”和脂蛋白“运输”的脂质。然而, 具有多不饱和脂肪酸酰基的CEs也存在氧化修饰机制, 能产生多种OxCEs, 这些OxCEs具有游离脂质的生物活性, 可以共价修饰蛋白质, OxCEs也是Ox-LDL和AS斑块主要成分^{[6, 23]}。

2 脂质组学

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脂质组学是代谢组学的重要分支, 是基于分析化学原理和技术手段, 特别是质谱技术, 通过定性定量分析生物样本中的脂质, 挖掘与其他脂质、蛋白质之间关系, 进而阐明相关的生物机制^[23]。脂质组学主要包括靶向脂质组学和非靶向脂质组学。前者主要用于信号处理的研究, 而后者在脂质代谢、分子机制和生物标志物的发现上应用前景广泛。

目前最常用两种脂质组学技术是shotgun MS和LC-MS。Shotgun MS方法是用高分辨率质谱将脂质粗提物不经分离直接质谱扫描, 这种方法依赖于离子阱或四极杆飞行时间(Q-TOF) 等高分辨率分析器, 由于缺乏色谱前分离, 部分牺牲了脂质提取物的复杂性。LC-MS脂质组学是色谱分离与质谱检测的耦合, 增加了额外的选择性, 引入保留时间作为鉴定的手段, 从而降低了质谱分析的复杂性, 并增加了每个样品的峰容量^{[24, 25]}。

脂质组学分析流程主要包括四方面: 样本采集、样本前处理、质谱数据采集和数据分析。①样本采集: 脂质组学生物样本可以是血液、血浆、血清、尿液、脑脊液、细胞、组织等。在样本采集时需要注意的是生物样品, 特别是组织, 需经过生理盐水灌流后取材, 液氮速冻, 以停止酶和化学降解过程。处理后样品应液氮或-80 ℃保存。②样本前处理: 通常用氯仿、甲基叔丁基醚(MTBE) 和庚烷萃取脂质。常用的有改良Bligh & Dyer法、改良Folch法、MTBE法和甲醇/丁醇法^[4]。在定量脂质组学分析时, 样本处理前添加适当的内标监测回收率和用于定量^{[4, 25]}, 例如商品化的氘代内标^{[24, 26]}。针对shotgun MS或针对特定脂类分析, 采用液/液或固相萃取分离极性和非极性脂类, 碱水解提取低丰度的鞘脂, 衍生化增加电离效率等方法来提高选择性和敏感性^[25]。一般选用极性溶剂(甲醇、乙腈、丙酮) 复溶样本待测。③质谱数据采集: 依次顺序为样品导入系统、离子源电离、质量分析器、检测器、数据处理系统。电喷雾电离质谱(ESI-MS) 在广谱的脂质组学分析中最常用, ESI是一种弱电离技术, 通常只产生分子离子峰[M+H]⁺, [M-H]^-, [M+Na]⁺适用于包括非极性脂类的多种生物分子^{[4, 25]}。④数据分析: 包括前体离子精确分子质量比对, 相似度匹配, 潜在脂质评分, 同位素重叠的反褶积, 和相对或绝对定量。适用于shotgun MS的专用软件有LipidXplorer (https://sourceforge.net/projects/lipidxplorer) 和ALEX (http://www.msLipidomics.info); 适用于LC-MS的有Lipid Search (赛默飞) 和LDA (http://genome.tugraz.at/lda); 以及两者均适用的开源的Lipid Blast (http://fiehnlab.ucdavis.edu/projects/LipidBlast/)。一般运用多元数据进行数据统计评价分析, 如非监督主成分分析(principal Component Analysis, PCA) 或正交偏最小二乘判别分析(orthogonal partial least squares discriminant analysis, OPLS-DA)^{[24, 25]}。

3 利用脂质组学发现冠心病脂质分子标志物

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目前研究发现一些特定种类的脂类, 与冠心病的严重程度及临床特征相关^{[6, 27]}。脂质组学技术正越来越多地被用于评估冠心病风险等^[7], 涉及脂质组学在临床研究中的应用见表 1^{[22, 28-39]}。此外动物实验模型中心脏、脂肪、肝脏等相关组织样本脂质组学研究成果也为脂质生物标志物提供了新的信息^[27]。研究表明, 不同种类Cer比值、超长Cer、S1P、缩醛磷脂、LPA、氧化脂质与冠心病密切相关, 未来可能作为疾病标志物用于评估冠心病的风险等级。

3.1 Cer、S1P与冠心病

多个临床研究表明较高的血浆Cer水平与AS、内脏肥胖、非酒精性脂肪肝和Ⅱ型糖尿病有关, 这些疾病都是冠心病的并发因素^[40]。长链Cer、极长链Cer和SM与不良的心脏预后有关。一项包括3 384例的临床研究发现血浆Cerd18∶1/16∶0、Cerd18∶1/18∶0、Cerd18∶1/24∶0和Cerd18∶1/24∶1水平是冠心病的危险标志物, 尤其Cerd18∶1/16∶0与Cerd18∶1/24∶0的比值是不依赖于其他脂质标志物和C反应蛋白的独立风险因素, 与冠心病全因死亡相关^[28]。有研究显示射血分数保留性心衰患者血中C16∶0-Cer和C18∶0-Cer显著增加^[29]。超长链Cer升高可诱导胰岛素抵抗、氧化应激、线粒体功能障碍和线粒体吞噬, 心衰患者心肌组织和血浆中超长链Cer显著增加^[41]; 相比之下, 另一项2 217名参与者的血浆研究发现含有C22∶0-Cer或C24∶0-Cer与降低冠心病发病率和全因死亡率有关, SPTLC3是鞘脂新生途径的限速酶SPT的一个亚型, 全基因组相关分析显示SPTLC3可能是C24∶0-Cer和C22∶0-Cer调节的潜在治疗靶点^[30]; 含有20-、22-或24-碳酰基链的SM也有类似的作用^[31]。心衰患者和缺血性心衰小鼠的循环和心脏Cer水平均升高^[32], 急性和慢性缺血性损伤中心肌Cer水平的增加都是由新生途径激活, 受Cer新生途径的限速酶SPT调控^{[32, 42]}。Cer的积累通过多种直接和间接机制损害线粒体功能, 从而损害心脏功能, 抑制脂肪酸氧化和激活凋亡级联^[33]。

与许多研究显示Cer是心血管病的诱导剂相反, Cer的磷酸化产物S1P似乎具有明显的心源性和心肌保护的特性。膜中性鞘磷脂酶(membraneneutralsphingomyelinase, nSMase) 和酸性鞘磷脂酶(acidic sphingomyelinase, aSMase) 水解SM释放Cer。在小鼠、兔和大鼠缺血再灌注损伤(IRI) 模型和多项心衰动物模型中均观察到Cer、nSMase和aSMase在血液、梗死部位或缺血后心脏中升高, 同时S1P降低; 可见Cer的积累可能是SM分解代谢引起的。而鞘氨醇SPH作为底物可生成Cer或S1P, SPH作为心脏保护剂还是心血管疾病诱导剂可能取决于其自身代谢命运^[6]。扩张型心肌病、糖尿病性心肌病、ACS和心肌炎患者Cer和SM的增加也常常伴随着S1P的减少。

3.2 缩醛磷脂类与冠心病

Sutter等^[34]研究发现4种缩醛磷脂(PC33∶1、PC33∶2、PC33∶3和PC35∶3) 水平的降低是稳定型冠心病和ACS的脂质特征。Meikle等^[35]对47例ACS和83例稳定型冠心病脂质组学研究显示, 较低水平的缩醛磷脂与较高的冠心病风险相关, 特别是ACS。

3.3 溶血磷脂类与冠心病

Sousa等^[43]分析H9c2大鼠心肌细胞缺血和/或饥饿模型的脂质谱发现, 缺血/饥饿条件下lysoPC (16∶0)、lysoPC (18∶1)、lysoPC (18∶0) 增加, CL (68∶4)、CL (72∶5)、CL (74∶7) 减少。高甘油三酯血症是冠心病的危险因素, Lee等^[36]报道了这类患者血浆lysoPC (14∶0)、lysoPC (16∶0) 显著增加, 这些信息可能有助于早期干预, 延缓疾病进展。

LPA是一种血小板激活剂, Dohi等^[44]对52例ACS患者切除的冠状动脉血栓和全身外周动脉血液样本分析发现, ACS患者冠状动脉血栓中LPA的含量明显高于体循环, 认为斑块中较高的LPA浓度与ACS的病理生理有关。研究显示LPA受体中LPAR1和LPAR3与心血管疾病关系更密切, LPAR1和LPAR3受体通过Akt和NFκB信号通路介导LPA诱导新生大鼠心肌细胞肥大; LPAR3通过激活Akt/mTOR通路参与心肌重塑和心肌梗死后的肥大; 目前认为, AS病变中LPA的产生是通过lysoGP的自身分化作用, 氧化低密度脂蛋白介导LPA诱导单核细胞黏附并导致AS^[17]。LPP3是LPA水解酶, 研究显示LPP3有助于抑制AS和/或稳定AS斑块, 而LPP3表达降低的个体发生AS及并发症的风险更高^[18]。

3.4 OxCE、OxPL与冠心病

大量研究表明非酶促氧化产物OxCE、OxPL与冠心病密切相关。Guo等^[37]发现心梗患者血浆中OxCE产物显著高于稳定型冠心病患者, 在这些氧化产物中, ch-13(c, t)-HODE是心肌梗死患者血浆中显著升高的主要成分之一; 研究^[21]表明, 在介入治疗时收集斑块组织, 靶向脂质组学发现斑块中含有丰富的氧化脂质, 其中, OxPL产物PONPC占比最多。OxPL产物中研究较多的有亚油酸磷脂类氧化产物OxPLPC和花生四烯酸磷脂类氧化产物OxPAPC。

Lu等^[38]使用靶向脂质组学来量化多种类型的OxCE, 检测了39名冠心病患者的血浆, 观察到心梗患者血浆中胆固醇花生四烯酸酯和胆固醇亚油酸酯的多重氧化产物明显高于对照组和其他心血管疾病组。这些OxCE是氧化特异性抗原决定簇, 能够启动内源性损伤相关分子模式(endogenous damage-associated molecular patterns, DAMPs) 通过Toll样受体-4 (Toll-like receptor 4, TLR4) 诱导巨噬细胞的炎症反应, 如胆固醇能与TLR4的辅因子髓样分化蛋白(myeloid differentiation-2, MD-2) 结合, 花生四烯酸胆固醇酯的氧化产物BEP-CE和最小修饰的LDL (mmLDL) 在巨噬细胞中能激活MD-2/TLR4/SYK途径, 导致ROS产生、炎症细胞因子分泌、介导巨噬细胞摄取Ox-LDL和泡沫细胞形成^{[45, 46]}; OxCEs也能激活内皮细胞, 但其对血管平滑肌细胞的作用尚未被研究^[23]。

PLPC是含有亚油酸的PL, 是脂蛋白颗粒中主要的含PUFA的PL之一, 其氧化产物二羰基脂醛同样能够启动DAMPs, 诱导巨噬细胞炎症反应, 参与泡沫细胞形成^{[6, 47]}。

PAPC是含有花生四烯酸的PL, 是细胞膜、肺表面活性物质和循环脂蛋白的组成成分。PAPC的sn-2不饱和链上发生氧化反应生成一种OxPL混合物, 统称为“oxPAPC”。在AS发展过程中, oxPAPC诱导吞噬细胞的高代谢、增强线粒体活性、稳定HIF-1α, 并促进IL-1β的表达。在AS、心肌缺血中促进炎症的启动和放大^[22]。OxPAPC产物中稳定的氧化产物如F2-IsoPs常被作为氧化应激的生物标志物; 小分子氧化产物丙二醛(MDA) 与4-ONE、4-HNE类似, 很容易和蛋白质或DNAs反应, 也是OSEs^[6]; OxPAPC产物POVPC、KOdiAPC, 是常见的内源性模式识别配体, 介导oxLDL与CD36或B类Ⅰ型清道夫受体的结合, 在泡沫细胞形成中发挥重要作用^[48]。

4 靶向脂质分子的冠心病药物研究

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目前, 靶向脂质分子调控作为冠心病药物的研发策略主要包括两个方面, 下调有害脂质分子, 研发相应的抑制剂、单克隆抗体、受体拮抗剂、靶向限速酶; 上调具有保护作用的脂质分子, 研发相应受体药物, 补充有益的脂质分子。

4.1 鞘脂类生物合成抑制剂

SPT是Cer生物合成的限速酶, 由SPTLC1、SPTLC2和SPTLC3三个亚基组成。Law等^[49]研究显示, 饱和脂肪配方喂养的小鼠诱发心肌肥厚和心肌功能障碍, 心肌Cer显著升高, 尤其是心肌内C14∶0-Cer以及超长链Cer特异性增加, 给予多球壳菌素后抑制了包括C14∶0-Cer在内的鞘脂的合成, 能恢复心脏功能。Yu等^[50]使用Cer抑制剂多球壳菌素和GSLs抑制剂d-PDMP干预高脂诱导的ApoE^-/-小鼠AS模型12周, 主动脉斑块大小分别减少了约35%和25%, 阿托伐他汀减少30%, 多球壳菌素显示出降低血清LDL-C和VLDL-C的温和能力, 而d-PDMP很少降低胆固醇水平; 而且与阿托伐他汀相比, 多球壳菌素表现出维持正常血糖稳态的优势; 多球壳菌素能下调单核细胞趋化蛋白1及其受体趋化因子受体2的表达, 在单核细胞招募中发挥关键作用, 并且减少具有促进炎症功能的Ly-6chigh单核细胞, 并通过下调CD36和ox-LDL受体-1 (LOX-1) 的表达来影响ox-LDL的摄取。这些研究结果揭示, 调节鞘脂合成可阻止脂质摄取和减少动脉壁炎症反应, 能有效缓解AS的进展。Krϋppel-like因子5 (KLF5) 是锌指转录因子, 通过直接激活PPARα调控心肌脂肪酸代谢, Hoffman等^[33]研究表明KLF5在人类和小鼠的缺血性心力衰竭心脏中KLF5显著增加, 并刺激Cer的生物合成, 是SPT的正向调控基因; 给予多球壳菌素干预可以抑制αMHC-rtTA-KLF5心梗小鼠SPT, 抑制心肌Cer水平, 减轻收缩功能障碍。由此可以看出, SPT酶抑制剂多球壳菌素有很大的发展潜力。

4.2 靶向S1P的药物

S1P是一种信号脂质, 在细胞中Cer经SphK1和SphK2激酶磷酸化产生S1P, S1P通过与细胞外伴侣结合后, 富集于循环中发挥作用, S1P是各种血管过程的重要媒介, 参与调节血管张力、内皮通透性、血管生成、高血压和动脉粥样硬化等生理病理过程^[51]。S1P受体(S1PR) 有三个亚型, 激活S1PR1似乎对心血管系统特别有益, 联合沉默S1PR2和S1PR3的小鼠发生缺血/再灌注损伤时, 梗死面积增加, 然而, 当S1PR2或S1PR3单独缺失时, 梗死面积没有改变; S1PR1 (S1P受体1) 特异性激动剂保护小鼠心肌细胞免受缺氧, 而S1PR1拮抗剂则有相反的作用^[52]。

靶向S1P调控目前主要有两种研究方向, S1PRs激活剂和SphK激酶抑制剂。目前已经上市或处于临床研究的S1PRs激活剂多用于治疗多发性硬化症和类风湿性关节炎等自身免疫性疾病, 如S1PR1、3、4、5的激活剂Fingolimod (FTY720, 已上市)^[51]。研究表明FTY720能够逆转主动脉缩窄术小鼠心肌肥厚和纤维化^[53], 降低猪缺血-再灌注损伤^[51], 改善心功能。两项临床试验^{[54, 55]}证实FTY720单独使用或联合用药能减轻缺血性卒中患者的出血和再灌注损伤, 改善急性缺血性卒中的临床疗效。但是临床应用发现FTY720会产生心动过缓的不良反应。新一代SP1R激动剂amiselimod (MT‐1303, Ⅱ期临床) 对S1PR1具有超高选择性, 对S1PR5具有强选择性, 对其他S1PR低选择或无影响, 避免了心动过缓^[56]。选择性Sphk1抑制剂PF543可以增加血管紧张素Ⅱ诱导的高血压模型小鼠的心肌S1P含量, 抑制心肌肥厚和内皮功能障碍^[57]。靶向S1P调控的amiselimod和PF543的作用还有待深入挖掘。

4.3 靶向LPA的药物

积累的研究显示LPA是血管炎症、AS治疗靶点。针对LPA调控治疗冠心病发展出不同的新药研发策略, 如使用ATX抑制剂降低LPA生成、LPA受体拮抗剂等^[58]。ATX是LPA产生的限速酶, 报道显示ATX抑制剂GLPG1690、BBT-877和BLD-04092已进入临床研究, GLPG1690在Ⅰ期临床中显著降低了血浆中18∶2 LPA浓度, 目前, 该药物已进入Ⅲ期临床试验^[58]。

LPA受体拮抗剂的研发最多, LPAR1受体拮抗剂BMS-986278、BMS-986020、BMS-986202和SAR100842目前已进入临床研究^[17], 主要用于治疗特发性肺纤维化和系统硬化症。

LPPs是LPA的水解酶, 在全基因组关联研究和一项对1 345名冠心病受试者的研究中发现, LPP3的位点rs17114036与心梗、不稳定心绞痛、中风和死亡等晚期心血管事件的风险有关。靶向LPP3调控促进LPA降解作为冠心病的药物研发策略目前已受到广泛关注^[59]。

5 总结与展望

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近年来, 随着分析技术的不断发展, 特别是质谱技术的进步, 能够识别和定量生物样本中种类繁多的脂质分子。脂质组学技术为生物活性脂类与疾病关系的研究开辟了一个新的、潜在的重要领域。脂质组学具有敏感、高通量和广泛覆盖能力等特点, 然而, 脂质组学中, 有两个瓶颈问题目前还无法突破, 一个是缺乏足够的参比化合物来验证色谱和质谱特性以及作为定量的内部标准, 这严重限制了对不常见和/或低丰度脂质分子的验证和定量; 另一个是对于脂质分子片段质谱的自动解译仍处于起步阶段。在任何脂质组学生物标志物搜索工作流程中, 这一任务都是手工完成的, 至今仍是最耗时、最费力的一步, 使得非靶向脂质组学生物标志物的搜索都是低通量的。

得益于脂质组学的发展, 人类AS病变、血浆、心脏等相关组织的脂质组成得以检测和量化, 越来越多的证据表明, 特殊种类的脂质分子与冠心病密切相关, 其中较高的Cer、SM水平尤其是长链、超长链Cer、LPA、小分子OxPL和OxCE等与冠心病风险正相关; 而缩醛磷脂、S1P、不饱和脂肪酸是心脏的保护剂; 目前, 如果要把这些脂质小分子纳入冠心病标志物, 急需标准化当前的质谱定量和分析方法, 这一点非常重要, 这样才可以分析大量的患者队列, 为冠心病的预防、诊断、药物研发提供更强有力的工具。

针对这些已有的研究结果, 也已经开展相关疾病的治疗干预尝试, 其中, 靶向SphK/S1P/S1PR轴的S1P调控, 靶向TAX/LPA/LPARs轴的LPA调控的药物研发发展最快, 有部分化合物已经上市或处于临床试验阶段, 由于脂质分子在组织中的广泛分布, 作用底物的非特异性, 第一代化合物有一些显而易见的不良反应, 随着研发的深入, 靶向性增加、微调控、低不良反应的新一代靶向脂质分子调控的药物将是未来冠心病药物的研发方向。

作者贡献: 杨冠林、翟琼负责综述的撰写与作图; 董馨、布仁、薛培凤负责综述部分内容的撰写与修改; 赵芳新负责综述的表格; 陆景坤负责综述的指导和修改。

利益冲突: 无任何利益冲突。

基金

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国家自然科学基金资助项目(81960757)
内蒙古自然科学基金项目(2019MS08119)
内蒙古自然科学基金面上项目(2020MS08045)
内蒙古自治区科技成果转化专项项目(2019CG042)
内蒙古医科大学面上项目(YKD2021MS033)

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https://doi.org/10.1016/j.atherosclerosis.2018.02.025

2022年第57卷第7期

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doi: 10.16438/j.0513-4870.2022-0280

接收时间：2022-03-02
首发时间：2025-12-23
出版时间：2022-07-12

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出版历史

收稿日期：2022-03-02
修回日期：2022-05-16

基金

国家自然科学基金资助项目(81960757)

内蒙古自然科学基金项目(2019MS08119)

内蒙古自然科学基金面上项目(2020MS08045)

内蒙古自治区科技成果转化专项项目(2019CG042)

内蒙古医科大学面上项目(YKD2021MS033)

作者信息

1.内蒙古医科大学基础医学院, 内蒙古自治区呼和浩特 010010

2.内蒙古医科大学药学院, 内蒙古自治区呼和浩特 010010

3.枣庄市肿瘤医院, 山东枣庄 277000

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*陆景坤, E-mail: 360569392@qq.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Clinical study	Sample (number)	Method	Finding	Reference
Angioplasty, PPCI	Plaque (12)	LC-MS/MS	The specific OxPL and OxCE were presented in plaque, and 1-palmitoyl-2-[9-oxo-nonanoyl] PC, represented a major phosphatidylcholine-OxPL molecule quantitated within plaque material	[22]
CAD	Plasma (3384)	UHPLC-MS	Cer (d18∶1/16∶0), Cer (d18∶1/18∶0), Cer (d18∶1/24∶0), and Cer (d18∶1/24∶1) are high-risk ceramides of CAD, and the Cer (d18∶1/16∶0)/Cer (d18∶1/24∶0) ratio is a lipid marker cardiovascular death	[28]
Heart failure	Serum (433)	LC-MS	Increased circulating concentration ceramides 16∶0 and 18∶0 are associated with HFpEF (heart failure with preserved ejection fraction)	[29]
CAD	Plasma (2217)	LC-MS	The specific very-long-chain fatty ceramides (C24∶0 and C22∶0) were associated with a reduced incidence of coronary heart disease and all-cause mortality. The SNPs of SPTLC3 (serine palmitoyltransferase long chain base subunit 3) were associated with plasma C22∶0 and C24∶0 ceramide concentrations	[30]
Diabetes, CVD, HF	Plasma (4612)	LC-MS	Higher levels of Cer-16 and SM-16 were associated with a higher risk of mortality, while higher levels of Cer-22, Cer-24, SM-20, SM-22, and SM-24 were associated with a lower risk of mortality	[31]
	Serum (64)	LC-MS	Patients with various stages of HF had increased circulating levels of ceramides, as well as elevated cardiac levels of ceramides, particularly long- and very long-chain species. Both mice and humans with HF had increased levels of SPTLC2	[32]
HF	Heart tissure (31)	LC-MS/MS	Certain ceramide species, such as Cer d18∶1/16∶0, Cer d18∶1/18∶1, and Cer d18∶1/24∶1 SPTLC1 and SPTLC2 expression were significantly increased in human ICM heart tissue samples	[33]
Stable CAD, AMI	Plasma (35)	LC-MS	Reduced levels of four PC plasmalogens (PC33∶1, PC33∶2, PC33∶3 and PC35∶3) were identified as a putatively novel lipid signature for CAD and AMI	[34]
ACS, CSA	Plasma (130)	LC-MS/MS	Compared with stable coronary artery disease, ACS plasma was lower in phospholipids including lyso species and plasmalogens, with the majority of lipid species differing in abundance located within high-density lipoprotein	[35]
Hypertriglyceridemia	Plasma (111)	UPLC-LTQ-Orbitrap MS	Compared with control group, lysoPCs, amides, and cis-4-octenedioic acid among non-diabetic and non-obese individuals with HTG had alterations	[36]
CHD, CHD+CBD, MI	Plasma (49)	LC-MS	The oxidation products of LA-CE and AA-CE in plasma of patients with MI increased, compared to control and other CVD groups. Among these oxidation products, ch-13(c, t)-HODE is one of the major components that are significantly elevated in plasma of MI patients	[37]
SA, MI	Plasma (28)	UHPLC-QTOF/MS	Oxidized PL and their hydrolyzed fatty acids were closely associated with CHD. These oxidative stress-induced LPO products overwhelmed the enzymatic products of arachidonic acid and linoleic acid, especially in plasma from MI patients. lysoPC (20∶0), lysoPC (20∶1), lysoPC (20∶2), lysoPC (20∶5), lysoPC (22∶5), lysoPE (18∶3), and glycerophosphocholine were differential metabolites in CHDs. Besides, lysoPA (18∶2) (one of the main lysoPA species) and lysoPS (20∶4) were increased in MI patients compared to healthy controls or SA patients	[38]
Autopsy or CAD	Plaque (4+4)	LC/ESI-MS/MS	A novel series of oxidation products containing the cyclopentenone moiety, termed deoxy-A2/J2-IsoP-PCs in vivo, which formed as intact phospholipids via free radical-catalyzed peroxidation of PAPC	[39]
CHD	Plasma (30)	LC/ESI-MS/MS	The levels of the total amounts of deoxy-A2/J2-IsoP-PC and deoxy-A2/J2-IsoPs were decreased in the plasma of CHD patients compared with the healthy subjects, consistent with a protective role of these compounds in cardiovascular diseases	[39]

Clinical study

Sample (number)

Method

Finding

Reference

Angioplasty, PPCI

Plaque (12)

LC-MS/MS

The specific OxPL and OxCE were presented in plaque, and 1-palmitoyl-2-[9-oxo-nonanoyl] PC, represented a major phosphatidylcholine-OxPL molecule quantitated within plaque material

[22]

CAD

Plasma (3384)

UHPLC-MS

Cer (d18∶1/16∶0), Cer (d18∶1/18∶0), Cer (d18∶1/24∶0), and Cer (d18∶1/24∶1) are high-risk ceramides of CAD, and the Cer (d18∶1/16∶0)/Cer (d18∶1/24∶0) ratio is a lipid marker cardiovascular death

[28]

Heart failure

Serum (433)

LC-MS

Increased circulating concentration ceramides 16∶0 and 18∶0 are associated with HFpEF (heart failure with preserved ejection fraction)

[29]

CAD

Plasma (2217)

LC-MS

The specific very-long-chain fatty ceramides (C24∶0 and C22∶0) were associated with a reduced incidence of coronary heart disease and all-cause mortality. The SNPs of SPTLC3 (serine palmitoyltransferase long chain base subunit 3) were associated with plasma C22∶0 and C24∶0 ceramide concentrations

[30]

Diabetes, CVD, HF

Plasma (4612)

LC-MS

Higher levels of Cer-16 and SM-16 were associated with a higher risk of mortality, while higher levels of Cer-22, Cer-24, SM-20, SM-22, and SM-24 were associated with a lower risk of mortality

[31]

Serum (64)

LC-MS

Patients with various stages of HF had increased circulating levels of ceramides, as well as elevated cardiac levels of ceramides, particularly long- and very long-chain species. Both mice and humans with HF had increased levels of SPTLC2

[32]

Heart tissure (31)

LC-MS/MS

Certain ceramide species, such as Cer d18∶1/16∶0, Cer d18∶1/18∶1, and Cer d18∶1/24∶1 SPTLC1 and SPTLC2 expression were significantly increased in human ICM heart tissue samples

[33]

Stable CAD, AMI

Plasma (35)

LC-MS

Reduced levels of four PC plasmalogens (PC33∶1, PC33∶2, PC33∶3 and PC35∶3) were identified as a putatively novel lipid signature for CAD and AMI

[34]

ACS, CSA

Plasma (130)

LC-MS/MS

Compared with stable coronary artery disease, ACS plasma was lower in phospholipids including lyso species and plasmalogens, with the majority of lipid species differing in abundance located within high-density lipoprotein

[35]

Hypertriglyceridemia

Plasma (111)

UPLC-LTQ-Orbitrap MS

Compared with control group, lysoPCs, amides, and cis-4-octenedioic acid among non-diabetic and non-obese individuals with HTG had alterations

[36]

CHD, CHD+CBD, MI

Plasma (49)

LC-MS

The oxidation products of LA-CE and AA-CE in plasma of patients with MI increased, compared to control and other CVD groups. Among these oxidation products, ch-13(c, t)-HODE is one of the major components that are significantly elevated in plasma of MI patients

[37]

SA, MI

Plasma (28)

UHPLC-QTOF/MS

Oxidized PL and their hydrolyzed fatty acids were closely associated with CHD. These oxidative stress-induced LPO products overwhelmed the enzymatic products of arachidonic acid and linoleic acid, especially in plasma from MI patients. lysoPC (20∶0), lysoPC (20∶1), lysoPC (20∶2), lysoPC (20∶5), lysoPC (22∶5), lysoPE (18∶3), and glycerophosphocholine were differential metabolites in CHDs. Besides, lysoPA (18∶2) (one of the main lysoPA species) and lysoPS (20∶4) were increased in MI patients compared to healthy controls or SA patients

[38]

Autopsy or CAD

Plaque (4+4)

LC/ESI-MS/MS

A novel series of oxidation products containing the cyclopentenone moiety, termed deoxy-A2/J2-IsoP-PCs in vivo, which formed as intact phospholipids via free radical-catalyzed peroxidation of PAPC

[39]

CHD

Plasma (30)

LC/ESI-MS/MS

The levels of the total amounts of deoxy-A2/J2-IsoP-PC and deoxy-A2/J2-IsoPs were decreased in the plasma of CHD patients compared with the healthy subjects, consistent with a protective role of these compounds in cardiovascular diseases

[39]