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: 8943776
• 负责人: Nona Sotoodehnia
• 金额: $ 73.52万
• 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/8943776
• 关键词: Accounting; Acids; Action Potentials; Address; Adult; Anabolism; Animal Model; Animals; Apoptosis; Arachidonic Acids; Arrhythmia; Autopsy; 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; Drug Targeting; Eicosanoids; Electrophysiology (science); Enzymes; Erythrocyte Membrane; Erythrocytes; Etiology; Evaluation; Fibrosis; Functional disorder; Gene Expression Profile; 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; Role; Sampling; Signal Transduction; Stratification; Stress; Tachyarrhythmias; Testing; Time; Tissues; Toxic effect; Transgenic Mice; Ventricular; Ventricular Fibrillation; Wild Type Mouse; Work; biochemical model; cell type; clinical material; combat; high risk; improved; innovation; modifiable risk; mortality; mouse model; new therapeutic target; novel; population based; prevent; protective effect; public health relevance; research study; response; small hairpin RNA; stressor; transcriptome sequencing

 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，仅在美国每年就导致多达40万人死亡。尽管多种分子途径、电生理特征和病理条件可以导致SCA，但临床和尸检研究一直表明在西方人群中存在一种主要的、常见的病理生理学。SCA最常见的电生理机制是室颤，最常见的病理基础是冠状动脉疾病(CAD)。尽管最近在治疗和预防冠心病方面取得了进展，但SCA仍然是导致死亡的主要原因之一。对于普通人群来说，预防SCA的有效方法很少，识别易患危及生命的心律失常的个体的线索也同样少。识别高危人群，发现新的心律失常防治靶点，对公共卫生具有重要意义。环氧乙烷三烯酸(Epoxyeicatrienoic acid，EETs)是细胞色素P450(CYP)酶介导的花生四烯酸重要的信号脂代谢产物。EETs对调节L型钙、钠、三磷酸腺苷依赖性钾通道维持正常的QT间期，减少缺血再灌注损伤后延长的QT间期具有电生理意义。它们还可以预防心肌肥厚时的室性快速性心律失常。在人类中，CYP2J2是心脏组织中负责EET生物合成的主要酶。CYP2J2在不同类型的细胞中有不同的调控，表达或活性下降会导致心肌细胞EETs降低，这可能导致毒性。我们发现小鼠红细胞中循环EETs与心脏组织EETs显著相关。此外，SCA患者的红细胞EETs显著低于对照组。本研究项目旨在验证EETs保护心肌组织免受缺血损伤和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EETs降低与SCA风险升高有关。这些假说将在以下三个目标中进行检验：目标1将在大样本的SCA患者和对照组中确定与SCA以及血浆和红细胞膜中循环EET相关的风险。目的2在转基因小鼠心肌组织中与野生型小鼠比较，确定EETs在长时间缺血和缺血加重心律失常中的保护作用的分子机制。目的研究细胞色素P450 2J2在缺血应激心肌细胞功能障碍中的下调作用，并首次确定与心肌细胞中细胞色素P450 2J2表达相关的基因组途径。这些目标的共同作用将有助于开发新的临床战略，通过改进风险分层和确定治疗和预防的新药物靶点来对抗SCA。