运用代谢组学手段研究ω-3多不饱和脂肪酸对急性心肌梗死患者预后的影响及相关分子机制

发布时间：2018-03-31 07:09

本文选题：急性心肌梗死　切入点：ω-3　出处：《天津医科大学》2017年博士论文

【摘要】：目的:急性心肌梗死(acute myocardial infarction,AMI)是冠状动脉急性、持续性缺血缺氧所引起的心肌坏死,常可危及生命,中国近年来本病发病呈明显上升趋势。已知ω-3多不饱和脂肪酸(polyunsaturated fatty acid,PUFAs)具有心血管保护作用,在体内主要通过环氧化酶(cyclooxygenase,COXs)、脂氧酶(lipoxygenase,LOXs)和细胞色素P450(cytochrome P450,CYP450)三条途径进行代谢,从而产生上百种不同生物活性的小分子物质。然而,其作用机制尚不明确。因此,运用代谢组学手段检测AMI发生时、药物治疗及同时补充ω-3PUFAs后PUFAs代谢产物的变化对探索其保护作用具有重要意义。内容:本课题拟运用代谢组学的方法,从整体了解在AMI发生时PUFAs代谢谱的异常变化及其与疾病进程的关系;同时,给予部分AMI患者补充ω-3 PUFAs,与常规治疗的AMI患者进行定期随访。通过相关临床检查和实验室检查观察其心功能、血管内皮功能、血浆炎症因子水平的改变,并运用代谢组学手段检测PUFAs代谢通路及相应代谢产物的变化,以期发现对心血管疾病有保护作用的代谢通路和(或)代谢产物,为心血管疾病诊断提供代谢标志物,为临床治疗提供新的思路和靶点。方法:1、选取于天津医科大学第二医院心内科住院且符合入选标准的AMI患者20例作为AMI组,以及同期冠状动脉造影完全正常的患者20例作为对照组。应用超高压液相色谱-串联质谱检测PUFAs各代谢产物含量,比较AMI组与对照组患者PUFAs代谢谱的异同。2、选取于天津医科大学第二医院心内科住院且符合入选标准的AMI患者60例。采用随机法分配,30例进行常规治疗作为对照组,30例在维持对照组治疗手段基础上加用ω-3 PUFAs作为ω-3组。应用临床检查及实验室检查观察两组患者心功能、血管内皮功能、血浆炎症因子水平的改变,并运用代谢组学方法检测PUFAs代谢谱的变化。结果:1、AMI组中花生四烯酸(arachidonic acid,ARA)经COX途径产生的6k-PGF1α降低,PGF2α、PGJ2升高;LOX途径中12-HETE、15-HETE、15-oxo-ETE、5-HETE、8-HETE、LTB4含量升高;P450途径中11,12-/14,15-/5,6-/8,9-DHET、19-HETE含量升高。DHA经LOX途径产生的10S,17S-DiHDoHE、20-HDoHE含量降低,14-HDoHE、RvD1含量升高;P450途径中16,17-EDP含量升高。EPA经COX途径产生的PGA3/B3/F3α含量升高;LOX途径中5-HEPE含量升高;P450途径中5,6-DiHETE含量升高。LA的代谢产物13-/9-HODE、12,13-/9,10-diHOME、12,13-/9,10-EpOME含量升高。其余代谢产物两组间无统计学差异。将代谢产物与AMI发生作相关性分析,15d-PGJ2、6k-PGF1α与AMI发生呈负相关;PGF2α、12-/15-/5-/8-HETE、15-oxo-ETE、LTB4、RvD1、PGA/B3、5,6-DiHETE、14,15-/5,6-/8,9-DHET、13-/9-HODE、12,13-/9,10-EpOME与AMI发生呈正相关;代谢产物间作相关性分析,PGF2α与其他产物关联度最高。2、对照组及ω-3组患者TCHO、LDL-c、hs-CRP水平降低,对照组hs-CRP降低幅度较ω-3组显著;ω-3组患者血浆NO水平升高,Apo B、Lp(a)水平降低。两组患者MACE、LVEF、LVSD、ADMA、FMD、IMT、血压及心率无统计学差异。对照组经治疗后PUFAs代谢谱中ARA经LOX途径的产物11-HETE、15-HETE、5-HETE含量降低,DHA经LOX途径的产物Maresin含量升高,ARA、EPA经CYP450途径的代谢产物EETs、EEQs含量降低。ω-3组ARA经COX途径的产物6k-PGF1α含量升高,PGF2α、PGJ2及LOX途径的产物LTB4含量降低。将NO水平与代谢产物作相关性分析,NO水平升高与DHA、6k-PGF1α呈正相关,与PGJ2呈负相关。结论:AMI患者PUFAs代谢谱与正常人群存在差异,其ARA代谢较为活跃。常规治疗及补充ω-3 PUFAs均可改善PUFAs代谢谱,而补充ω-3 PUFAs可通过维持6k-PGF1α与PGF2α、PGJ2、LTB4之间的平衡使得AMI患者更加获益。提示,ω-3 PUFAs是通过影响代谢产物发挥保护心血管系统的作用,而非其自身。
[Abstract]:Objective: acute myocardial infarction (acute myocardial, infarction, AMI) is coronary artery acute, persistent ischemia caused by myocardial necrosis, often life-threatening, Chinese in recent years, the onset of the disease was significantly increased. The known -3 polyunsaturated fatty acid (polyunsaturated fatty, acid, PUFAs) has cardiovascular protective effects in in vivo mainly through the cyclooxygenase (cyclooxygenase, COXs), Lipoxygenase (lipoxygenase, LOXs) and cytochrome P450 (cytochrome P450 CYP450) three metabolism of small molecules to produce hundreds of different biological activity. However, the mechanism is still not clear. Therefore, the use of metabonomics method detection of AMI occurs, the changes of drug treatment and -3PUFAs PUFAs after adding Omega metabolites on it is of great significance to explore its protective role. Content: this project intends to use metabonomics method, from the whole. Solution of abnormal changes in AMI occurred when the PUFAs metabolic spectrum and its relationship with the course of disease; at the same time, give some AMI patients of Omega -3 PUFAs, and the conventional treatment of AMI patients were followed up regularly. Through clinical examination and laboratory examination to observe the cardiac function and vascular endothelial function, plasma levels of inflammatory cytokine changes, and changes by using the metabonomics method to detect PUFAs metabolic pathway and corresponding metabolic products, in order to find the metabolic pathways that have protective effects on cardiovascular disease (or) metabolites, provide metabolic markers for diagnosis of cardiovascular diseases, to provide new ideas and targets for clinical treatment. Methods: 1, selected from the Department of Cardiology of Second Hospital Affiliated to Tianjin Medical University and the hospital meet the criteria of 20 AMI patients as AMI group, and the same period completely normal coronary angiography in 20 patients as the control group. The application of ultra high pressure liquid chromatography The PUFAs series mass spectrometric detection of metabolites between AMI group and control group of patients with PUFAs metabolic profiles of.2, selected from the Department of Cardiology of Second Hospital Affiliated to Tianjin Medical University Hospital of 60 patients with AMI and in accordance with the inclusion criteria were randomly assigned patients. In 30 cases, conventional therapy as the control group, 30 cases in the control group was maintained on the basis of treatment using -3 PUFAs as the Omega Omega -3 group. Two groups were observed in patients with cardiac function by clinical examination and laboratory examination, vascular endothelial function, plasma levels of inflammatory cytokine changes, and by using the metabonomics method to detect changes in PUFAs metabolism spectrum. Results: 1, four arachidonic acid in group AMI (arachidonic acid ARA) produced by the COX pathway 6k-PGF1 alpha PGF2 alpha, PGJ2 decreased, 12-HETE increased; LOX pathway in 15-HETE, 15-oxo-ETE, 5-HETE, 8-HETE, P450, LTB4 content increased; 11,12-/14,15-/5,6-/ 8,9-DHET pathway, increased the content of 19-HETE.DHA The LOX pathway of 10S, 17S-DiHDoHE, 14-HDoHE, 20-HDoHE content decreased, RvD1 content increased; the content of 16,17-EDP in the P450 pathway increased PGA3/B3/F3 alpha.EPA content produced by the COX pathway increased; increase the content of 5-HEPE in the LOX pathway; the content of 5,6-DiHETE in the P450 pathway increased the metabolites of.LA 13-/9-HODE, 12,13-/9,10-diHOME, 12,13-/9,10-EpOME content increased. The remaining metabolites no significant difference between the two groups. The metabolites and AMI correlation analysis, 15d-PGJ2,6k-PGF1 alpha and AMI had a negative correlation; 12-/15-/5-/8-HETE, 15-oxo-ETE, PGF2 alpha, LTB4, RvD1, PGA/B3,5,6-DiHETE, 14,15-/5,6-/8,9-DHET, 13-/9-HODE, 12,13-/9,10-EpOME and AMI were positively correlated; for correlation analysis of metabolites, PGF2 alpha and other products association the highest.2, the control group and the Omega -3 groups TCHO, LDL-c, hs-CRP decreased, hs-CRP decreased compared with the control group -3. Group was significantly increased; Omega -3 group of plasma NO levels in patients with Apo B Lp (a) levels decreased. Two groups were MACE, LVEF, LVSD, ADMA, FMD, IMT, no significant difference in blood pressure and heart rate in control group. After treatment, the metabolism of PUFAs in ARA spectra by LOX pathway product 11-HETE, 15-HETE, 5-HETE the content decreased, DHA content of product Maresin LOX pathway increased, ARA, EPA via the CYP450 pathway metabolite of EETs, decreased the content of EEQs. -3 ARA 6k-PGF1 products by Omega group alpha in the COX pathway increased, PGF2 alpha, PGJ2 and LOX decreased the content of product LTB4 pathway. NO level and metabolic product correlation analysis of elevated levels of NO and DHA, 6k-PGF1 showed positive correlation, and negatively correlated with PGJ2. Conclusion: AMI patients with PUFAs metabolic differences with the normal group, the ARA metabolism is more active. The conventional treatment and supplemental Omega -3 PUFAs can improve the metabolism of PUFAs spectrum, and added Omega -3 PUFAs can maintain 6k-PGF1 and alpha PGF2 alpha PGJ. 2, the balance between LTB4 makes AMI patients benefit more. It suggests that Omega -3 PUFAs plays the role of protecting the cardiovascular system by affecting the metabolites, not itself.

【学位授予单位】：天津医科大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R542.22

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