CYP2J2 Mediated Eicosanoids in Arrhythmias and Sudden Cardiac Arrest

CYP2J2 介导的类二十烷酸在心律失常和心脏骤停中的作用

• 批准号: 9281892
• 负责人: Nona Sotoodehnia
• 金额: $ 72.11万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-21 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9281892
• 关键词: Accounting; Acids; Action Potentials; Address; Adult; Anabolism; Animal Model; Animals; Apoptosis; Arachidonic Acids; Arrhythmia; Autopsy; Biological; CYP2J2 gene; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Myocytes; Case-Control Studies; Cell Survival; Cell membrane; Cell model; Cells; Cellular biology; Cessation of life; Characteristics; Chronic; Clinical; Cohort Studies; Complement; Complex; Coronary Arteriosclerosis; Cytochrome P450; Data; Down-Regulation; Eicosanoids; Electrophysiology (science); Enzymes; Erythrocyte Membrane; Erythrocytes; Etiology; Evaluation; Fibrosis; Functional disorder; General Population; Genes; Genomics; Heart Arrest; Heart Hypertrophy; Hospitals; Human; Hypoxia; Individual; Infarction; Injury; Ischemia; Lead; Life; Link; Lipids; Literature; Measures; Mediating; Membrane; Molecular; Mus; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Oxidative Stress; Pathologic; Pathway interactions; Patients; Phase; Phenotype; Plasma; Population; Predisposition; Prevention; Public Health; Publishing; Reactive Oxygen Species; Regulation; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Research Project Grants; Risk; Risk Factors; Risk stratification; Role; Sampling; Signal Transduction; Stress; Tachyarrhythmias; Testing; Time; Tissues; Toxic effect; Transgenic Mice; Ventricular; Ventricular Fibrillation; Wild Type Mouse; Work; biochemical model; cell type; clinical material; combat; experimental study; high risk; improved; innovation; modifiable risk; mortality; mouse model; multidisciplinary; new therapeutic target; novel; population based; prevent; prospective; protective effect; public health relevance; response; small hairpin RNA; stressor; transcriptome; transcriptome sequencing; treatment group; Accounting; Acids; Action Potentials; Address; Adult; Anabolism; Animal Model; Animals; Apoptosis; Arachidonic Acids; Arrhythmia; Autopsy; Biological; CYP2J2 gene; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Myocytes; Case-Control Studies; Cell Survival; Cell membrane; Cell model; Cells; Cellular biology; Cessation of life; Characteristics; Chronic; Clinical; Cohort Studies; Complement; Complex; Coronary Arteriosclerosis; Cytochrome P450; Data; Down-Regulation; Eicosanoids; Electrophysiology (science); Enzymes; Erythrocyte Membrane; Erythrocytes; Etiology; Evaluation; Fibrosis; Functional disorder; General Population; Genes; Genomics; Heart Arrest; Heart Hypertrophy; Hospitals; Human; Hypoxia; Individual; Infarction; Injury; Ischemia; Lead; Life; Link; Lipids; Literature; Measures; Mediating; Membrane; Molecular; Mus; Muscle Cells; Myocardial Infarction; Myocardial Ischemia; Oxidative Stress; Pathologic; Pathway interactions; Patients; Phase; Phenotype; Plasma; Population; Predisposition; Prevention; Public Health; Publishing; Reactive Oxygen Species; Regulation; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Research Project Grants; Risk; Risk Factors; Risk stratification; Role; Sampling; Signal Transduction; Stress; Tachyarrhythmias; Testing; Time; Tissues; Toxic effect; Transgenic Mice; Ventricular; Ventricular Fibrillation; Wild Type Mouse; Work; biochemical model; cell type; clinical material; combat; experimental study; high risk; improved; innovation; modifiable risk; mortality; mouse model; multidisciplinary; new therapeutic target; novel; population based; prevent; prospective; protective effect; public health relevance; response; small hairpin RNA; stressor; transcriptome; transcriptome sequencing; treatment group

 DESCRIPTION (provided by applicant): Sudden cardiac arrest (SCA) is a major public health concern, accounting for up to 400,000 annual deaths in the US alone. Although a variety of molecular pathways, electrophysiologic characteristics, and pathologic conditions can result in SCA, clinical and autopsy studies have consistently demonstrated a predominant, common pathophysiology in Western populations. The most common electrophysiologic mechanism for SCA is ventricular fibrillation and the most common pathologic substrate is coronary artery disease (CAD). Despite recent progress in treatment and prevention of CAD, SCA continues to be one of the leading causes of mortality. There are few effective approaches to SCA prevention for the general population and equally few clues to identify individuals predisposed to life-threatening arrhythmias. Identifying those at increased risk, and discovering novel therapeutic targets for arrhythmia prevention and treatment is of great public health importance. Epoxyeicsatrienoic acids (EETs) are important signaling lipid metabolites of arachidonic acid mediated by cytochrome P450 (CYP) enzymes. EETs have electrophysiological significance in regulating L-type Ca2+, Na+ and ATP dependent K+ (KATP) channels that maintain a normal QT-period and reduce the prolonged QT period following ischemia reperfusion injury. They also protect against ventricular tachyarrhythmia during cardiac hypertrophy. In humans CYP2J2 is the main enzyme responsible for EET biosynthesis in cardiac tissue. CYP2J2 is differentially regulated in various cell types and decline in expression or activity results in lower EETs in cardiomyocytes, which can lead to toxicity. We discovered that circulating EETs in erythrocytes were significantly correlated with cardiac tissue EETs in mice. In addition, erythrocyte EETs were significantly lower in SCA patients than controls. This research project aims to test the hypothesis that EETs protect cardiac tissue from ischemic injury as well as lethal ischemia-triggered arrhythmias. We also hypothesize that lower EETs in circulating plasma or erythrocyte membranes are associated with higher risk of SCA. These hypotheses will be tested in three aims as follows; Aim 1 will determine the risk associated with SCA and circulating EETs in plasma and RBC membranes in a large sample of SCA patients and controls. Aim 2 will determine the molecular mechanism for EETs' protective effect during prolonged ischemia and ischemia potentiated arrhythmias in a transgenic mouse model expressing human CYP2J2 in cardiac tissue vs. wild type mice. Aim 3 will test the role of CYP2J2 down regulation in cardiomyocyte dysfunction during ischemic stress and for the first time, determine the genomic pathways associated with the expression of CYP2J2 in ventricular myocytes. These aims together will aid in developing new clinical strategies to combat SCA by improved risk stratification and identification of novel drug targets for treatment and prevention.

 描述（由适用提供）：心脏骤停（SCA）是一个主要的公共卫生问题，仅在美国，每年最高可达400,000例死亡。尽管各种分子途径，电生理特征和病理状况可能导致SCA，但临床和尸检研究始终显示出西方人群中主要的常见病理生理学。 SCA最常见的电生理机制是心室纤颤，最常见的病理底物是冠状动脉疾病（CAD）。尽管最近在治疗和预防CAD方面取得了进展，但SCA仍然是死亡率的主要原因之一。对于普通人群而言，几乎没有有效的SCA预防方法，也很少有线索可以识别出易于威胁生命的心律失常的个体。确定风险增加的人，发现新型疗法环氧酸性酸（EET）是重要的信号传导脂质代谢产物的脂肪代谢产物，这是由细胞色素P450（CYP）酶介导的。 EET在调节L型Ca2+，Na+和ATP依赖性K+（KATP）通道方面具有电生理学意义，该通道保持正常的QT-周期并减少缺血再融合损伤后的延长QT期。它们还可以在心脏肥大期间预防心室心律失常。在人类中，CYP2J2是负责心脏组织中EET生物合成的主要酶。 CYP2J2在各种细胞类型中受到差异调节，表达或活性下降导致心肌细胞中的EET较低，这可能导致毒性。我们发现红细胞中的循环EET与小鼠的心脏组织EET显着相关。此外，SCA患者的红细胞EET明显低于对照组。该研究项目旨在检验以下假设：EET保护心脏组织免受缺血性损伤以及致死性缺血触发的心律不齐。我们还假设循环血浆或红细胞膜中的较低的EET与SCA的较高风险有关。这些假设将在三个目标中进行以下测试； AIM 1将确定大量SCA患者和对照样本中血浆和RBC机制中与SCA和循环EET相关的风险。 AIM 2将确定在长期缺血和缺血潜在心律不齐期间Eets受保护作用的分子机制，在心脏组织中表达人CYP2J2的转基因小鼠模型与野生型小鼠。 AIM 3将测试CYP2J2降低调节在缺血性胁迫期间心肌细胞功能障碍中的作用，并首次确定与心室心肌细胞中CYP2J2相关的基因组途径。这些目标将共同开发新的临床策略，通过改善风险分层并确定新型药物靶标在治疗和预防方面。