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

 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（由申请人提供）：心脏骤停 (SCA) 是一个主要的公共卫生问题，仅在美国每年就有多达 40 万人死亡。尽管多种分子途径、电生理特征和病理状况均可导致 SCA，但临床和尸检研究一致证明西方人群中存在一种占主导地位的常见病理生理学。 SCA 最常见的电生理机制是心室颤动，最常见的病理基础是冠状动脉疾病 (CAD)。尽管最近在 CAD 的治疗和预防方面取得了进展，但 SCA 仍然是导致死亡的主要原因之一。对于一般人群来说，预防 SCA 的有效方法很少，而且识别易患危及生命的心律失常的个体的线索也同样很少。识别高风险人群并发现心律失常预防和治疗的新治疗靶点对于公共卫生具有重要意义。环氧二十碳三烯酸 (EET) 是由细胞色素 P450 (CYP) 酶介导的花生四烯酸的重要信号脂质代谢物。 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，这些通道可维持正常的 QT 期并减少缺血再灌注损伤后 QT 期延长。它们还可以防止心脏肥大期间发生室性快速心律失常。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性调节，表达或活性下降会导致心肌细胞中的 EET 降低，从而导致毒性。我们发现红细胞中的循环 EET 与小鼠心脏组织 EET 显着相关。此外，SCA 患者的红细胞 EET 显着低于对照组。该研究项目旨在验证 EET 可以保护心脏组织免受缺血性损伤以及致命性缺血引发的心律失常的假设。我们还假设循环血浆或红细胞膜中较低的 EET 与较高的 SCA 风险相关。这些假设将在以下三个目标中进行检验：目标 1 将确定大量 SCA 患者和对照样本中与 SCA 以及血浆和红细胞膜中循环 EET 相关的风险。目标 2 将确定在心脏组织中表达人 CYP2J2 的转基因小鼠模型中，与野生型小鼠相比，EET 在长时间缺血和缺血增强性心律失常期间的保护作用的分子机制。目标 3 将测试 CYP2J2 下调在缺血应激期间心肌细胞功能障碍中的作用，并首次确定与心室肌细胞中 CYP2J2 表达相关的基因组通路。这些目标共同将有助于制定新的临床策略，通过改进风险分层和识别新的治疗和预防药物靶点来对抗 SCA。