Metabolomics study in patients post myocardial infarction

心肌梗死后患者的代谢组学研究

• 批准号: 9892972
• 负责人: Nipavan Chiamvimonvat
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892972
• 关键词: Acids; Acute myocardial infarction; Animal Model; Animals; Anti-Inflammatory Agents; Apoptosis; Arachidonic Acids; Arrhythmia; Biological Markers; Cancer Center; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chest; Clinic; Clinical; Consent; Control Groups; Coronary; Coupled; Cytochrome P450; Data; Depressed mood; Echocardiography; Eicosanoids; Enrollment; Entomology; Enzyme Inhibitor Drugs; Enzymes; Epoxide hydrolase; Evolution; Exhibits; Fibroblasts; Fibrosis; Heart; Heart Hypertrophy; Heart Injuries; Heart failure; Hospitals; Hypertrophy; Inflammatory; Left Ventricular Ejection Fraction; Lipids; Long-Term Effects; Longitudinal prospective study; M-Mode Echocardiography; Malignant - descriptor; Malignant Neoplasms; Medical center; Medicine; Metabolic; Metabolism; Microvascular Dysfunction; Modeling; Morbidity - disease rate; Muscle Cells; Mutation; Myocardial Infarction; Myocarditis; Oryctolagus cuniculus; Outcome; Pathway interactions; Patients; Physicians; Play; Prevention; Property; Proteins; Recovery; Resolution; Risk; Role; Scientist; Signal Pathway; Stimulus; Stress; Testing; Translating; Ventricular; Veterans; bench to bedside; chemokine; clinically relevant; coronary fibrosis; cytokine; endoplasmic reticulum stress; follow-up; high risk; improved; inhibitor/antagonist; insight; lipid mediator; metabolomics; mortality; multidisciplinary; novel; pressure; prevent; response; therapeutic target; volunteer

ABSTRACT This proposal represents a bench-to-bedside study to translate our recent findings in small animal models into the clinic. Cardiac remodeling is the heart’s prevailing response to extrinsic and intrinsic stimuli including pressure or volume overload, mutations of sarcomeric proteins, or loss of contractile mass from myocardial infarction (MI). Adverse cardiac remodeling is driven at the cellular level by myocyte hypertrophy, apoptosis, microvascular dysfunction, fibrosis, and electrical perturbations. Our group was the first to demonstrate beneficial effects of a novel class of soluble epoxide hydrolase (sEH) inhibitors in clinically relevant models of cardiac hypertrophy and failure. SEH is a critical enzyme in the cytochrome P450 pathway. Treatment with sEH inhibitors (sEHIs) results in the prevention of ventricular myocyte hypertrophy and electrical remodeling in pressure overload and myocardial infarction models. Our findings further demonstrate that treatment with sEHIs prevents cardiac fibroblast proliferation and fibrosis. This project is focused on the novel concept that pro-inflammatory metabolites of the cytochrome P450 pathway can result in adverse cardiac remodeling by increasing cardiac myocyte hypertrophy, apoptosis, coupled with a persistent increase in cytokines and chemokines leading to an increase in cardiac fibrosis. Hence, the main objective of this proposal is to use novel metabolomic profiling to determine the mechanistic roles of lipid mediators in adverse cardiac remodeling in patients post MI. New treatment paradigms for adverse cardiac remodeling are likely to be highly impactful.

摘要 这项提议代表了一项从实验室到床边的研究，以转化我们最近在小动物模型中的发现 进了诊所心脏重构是心脏对外在和内在刺激的主要反应， 压力或容量超负荷，肌节蛋白突变，或心肌收缩质量损失 心肌梗死（MI）。不利的心脏重塑在细胞水平上由肌细胞肥大、凋亡， 微血管功能障碍、纤维化和电扰动。我们组是第一个 一类新型可溶性环氧化物水解酶（sEH）抑制剂在临床相关模型中的有益作用 心脏肥大和衰竭。SEH是细胞色素P450途径中的关键酶。治疗 sEH抑制剂（sEHI）可预防心肌细胞肥大和电重构， 压力超负荷和心肌梗死模型。我们的研究结果进一步表明， sEHI可防止心脏成纤维细胞增殖和纤维化。这个项目的重点是新的概念， 细胞色素P450途径的促炎代谢物可通过以下途径导致不利的心脏重塑： 增加心肌细胞肥大、凋亡，伴随细胞因子持续增加， 导致心脏纤维化增加的趋化因子。因此，本提案的主要目的是利用 一种新的代谢组学分析，以确定脂质介质在不良心脏重塑中的机制作用 在MI后患者中。不良心脏重塑的新治疗范式可能具有高度影响力。