Characterization And Functional Significance Of P450 Arachidonate Epoxygenases

P450 花生四烯酸环氧合酶的特征和功能意义

• 批准号: 10919036
• 负责人: Darryl C Zeldin
• 金额: $ 98.92万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10919036
• 关键词: 2019-nCoV; Acids; Action Potentials; Affect; Alteplase; Anabolism; Anatomy; Antiinflammatory Effect; Apoptosis; Arachidonic Acids; Area; Atherosclerosis; Biochemical; Blood Vessels; COVID-19; CYP2C19 gene; CYP2J2 gene; CYP2J5 gene; Cardiac; Cardiac Electrophysiologic Techniques; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Adhesion Molecules; Cytochrome P450; Eicosanoids; Endothelial Cells; Endothelium; Enzymes; Epoxide hydrolase; Evaluation; Exhibits; Gene Expression; Genes; Genetic Polymorphism; Glycols; Goals; Growth; Heart; Human; Hydrolase; Hydrolysis; Hypertension; Hypoxia; Injury; Ischemia; Kidney; Kidney Diseases; Knockout Mice; Left Ventricular Function; Malignant Neoplasms; Microsomal Epoxide Hydrolase; Molecular; Mus; Myocardial Ischemia; Myosin Heavy Chains; Nitric Oxide; Pathway interactions; Physiology; Recovery; Recovery of Function; Renal function; Research; Retina; Role; SARS coronavirus; Severe Acute Respiratory Syndrome; Sodium-Restricted Diet; Tennessee; Transgenic Mice; Tumor Promotion; Variant; Vascularization; Vasodilator Agents; Ventricular Cardiac alpha-Myosin; Work; angiogenesis; animal model selection; arachidonate; attenuation; beta-adrenergic receptor; cardiovascular disorder risk; cohort; cytokine; cytokine release syndrome; eicosanoid metabolism; heart function; human coronavirus; human disease; human model; improved; in vivo; inhibitor; ischemic injury; multi-ethnic; novel coronavirus; promoter; vascular smooth muscle cell migration

Cytochromes P450 metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) which have potent effects on cardiovascular and renal function. EETs are metabolized to corresponding diols (DHETs) by microsomal epoxide hydrolase (mEH) and soluble epoxide hydrolase (sEH). Current research involves: (1) characterization of CYP2J and CYP2C subfamily P450s at the biochemical and molecular levels; (2) evaluation of the functional roles of CYP2J products in cardiovascular and renal physiology; (3) evaluation of the functional roles of epoxide hydrolases in cardiovascular physiology; (4) examination of this pathway in selected animal models of human disease (ischemic heart disease, hypertension, atherosclerosis, cancer), and (5) evaluation of the effect of human polymorphisms in genes for CYP2C, CYP2J, sEH and mEH on cardiovascular function and disease. We have discovered a number of mammalian CYP2Js, although we have focused most of our efforts on human CYP2J2 and mouse CYP2J5. Human CYP2J2 is the major human P450 expressed in heart and vasculature, where it is localized to cardiac myocytes and endothelial cells, and is active in the metabolism of AA to EETs. CYP2J2-derived EETs are vasodilators, inhibit cytokine-induced endothelial cell adhesion molecule expression, induce tissue plasminogen activator gene expression, inhibit vascular smooth muscle cell migration, protect endothelial cells against hypoxia-reoxygenation injury and apoptosis, upregulate endothelial nitric oxide biosynthesis, affect cardiac electrophysiology, and protect the heart from ischemic injury. CYP2J2 transgenic mice (alpha-myosin heavy chain promoter driven cardiac-specific expression) were developed to study the effects of increased EETs on cardiac function in vivo. These mice have normal basal heart anatomy and function, improved post-ischemic left ventricular function, shortened cardiac action potential, altered cardiac electrophysiology, and enhanced beta-adrenergic receptor responsiveness. Similarly, sEH null mice which exhibit reduced EET hydrolysis have improved postischemic functional recovery. We discovered that mEH regulates EET levels in vivo and that hearts from mEH/sEH double-null mice have greater recovery of heart function relative to hearts from sEH null mice. We have also developed transgenic mice in which CYP2J2, CYP2C8 or sEH are expressed exclusively in endothelial cells (Tie2 promoter driven) to examine the role of these enzymes and their products on vascular function. Endothelial expression of CYPs or sEH regulate angiogenesis which promotes tumor formation and growth and regulates retinal vascularization. The human CYP2J2 gene has been cloned, sequenced and characterized. We have identified several functionally relevant CYP2J2 polymorphic variants, one of which is associated with reduced CYP2J2 expression and is associated with risk of cardiovascular disease in several cohorts. We have also identified functionally relevant polymorphisms in the sEH gene and have shown that they are associated with cardiovascular disease risk in a large multiethnic cohort in the U.S. CYP2J5 is a major murine P450 arachidonic acid epoxygenase expressed in the kidney and localized to proximal tubules. CYP2J5 null mice have spontaneous hypertension that persists on both high and low salt diets. Consistent with these findings, we have shown that there is an association between CYP2J2 polymorphic variants and hypertension in a cohort from Tennessee. Given the anti-inflammatory effects of sEH inhibitors (sEHis), we have examined the role of sEHis in attenuation of SARS-CoV-2-induced eicosanoid and cytokine storm. This project involves research on human coronavirus, novel coronavirus, COVID-19, Severe Acute Respiratory Syndrome coronavirus disease, SARS coronavirus, SARS-coronavirus-2, SARS-cov-2, SARS-cov2, SARS-related coronavirus 2, Severe acute respiratory syndrome coronavirus 2, SARS-Associated Coronavirus, SARS-cov, or SARS-Related Coronavirus.

细胞色素P450代谢蛛网膜酸（AA）为环氧卫生酸（EET），对心血管和肾功能具有有效作用。通过微粒体环氧化物水解酶（MEH）和可溶性环氧化物水解酶（SEH）代谢为相应的二醇（DHET）。 当前的研究涉及：（1）在生化和分子水平上表征CYP2J和CYP2C亚家族P450； （2）评估CYP2J产品在心血管和肾脏生理学中的功能作用； （3）评估环氧化物水解酶在心血管生理学中的功能作用； （4）检查人类疾病的选定动物模型（缺血性心脏病，高血压，动脉粥样硬化，癌症）和（5）评估人类多态性对CYP2C，CYP2J，SEH和MEH对心血管功能和疾病的影响。我们发现了许多哺乳动物CYP2J，尽管我们将大部分精力集中在人CYP2J2和小鼠CYP2J5上。人CYP2J2是在心脏和脉管系统中表达的主要人类P450，它位于心肌细胞和内皮细胞中，并且活跃于AA代谢为EET为EET的代谢。 CYP2J2-derived EETs are vasodilators, inhibit cytokine-induced endothelial cell adhesion molecule expression, induce tissue plasminogen activator gene expression, inhibit vascular smooth muscle cell migration, protect endothelial cells against hypoxia-reoxygenation injury and apoptosis, upregulate endothelial nitric oxide biosynthesis, affect cardiac electrophysiology,并保护心脏免受缺血伤害。开发了CYP2J2转基因小鼠（α-肌球蛋白重链启动子驱动的心脏特异性表达），以研究增加Eets对体内心脏功能的影响。这些小鼠具有正常的基础心脏解剖结构和功能，缺血后左心室功能改善，心脏作用缩短，心脏电生理学改变以及增强的β-肾上腺素能受体反应性。同样，表现出降低EET水解的SEH无效小鼠也改善了缺血后的功能恢复。我们发现MEH在体内调节EET水平，而MEH/SEH双重无效小鼠的心脏相对于来自SEH无效小鼠的心脏功能的恢复更大。我们还开发了转基因小鼠，其中CYP2J2，CYP2C8或SEH仅在内皮细胞（TIE2启动子驱动）中仅表达，以检查这些酶及其产物在血管功能上的作用。 CYP或SEH的内皮表达调节血管生成，该血管生成促进肿瘤形成和生长，并调节视网膜血管形成。人CYP2J2基因已被克隆，测序和表征。我们已经确定了几种与功能相关的CYP2J2多态性变体，其中一种与CYP2J2的表达降低有关，并且与几个同类群体中心血管疾病的风险有关。我们还确定了SEH基因中与功能相关的多态性，并表明它们与美国大型多种族队列中的心血管疾病风险相关，CYP2J5是肾脏中表达的主要鼠P450蛛网膜酸性酸环氧酶，在肾脏中表达并局部用于邻近的小气囊。 CYP2J5无效小鼠的自发性高血压持续在高盐饮食和低盐饮食上。与这些发现一致，我们已经表明，田纳西州的同伴中CYP2J2多态性变体与高血压之间存在关联。鉴于SEH抑制剂（SEHI）的抗炎作用，我们研究了SEHI在SARS-COV-2-2诱导的eicosanoid和cytokine风暴中的作用。 该项目涉及研究人类冠状病毒，新型冠状病毒，Covid-19，严重急性呼吸综合症冠状病毒疾病，SARS冠状病毒，SARS-Coronavirus-2，SARS-COVIRUS-2，SARS-COV-2，SARS-COV-2，SARS-COV2，SARS-COV2，SARS-SARS-COVIRUS 2，与SARS COTIROTIAL CONAVIRUS 2，严重的急性呼吸道呼吸道综合征2与SARS相关的冠状病毒。

项目成果

Differential effects of soluble epoxide hydrolase inhibition and CYP2J2 overexpression on postischemic cardiac function in aged mice.

• DOI: 10.1016/j.prostaglandins.2012.08.001
• 发表时间: 2013-07
• 期刊: Prostaglandins & other lipid mediators
• 影响因子: 2.9
• 作者: Chaudhary KR;Zordoky BN;Edin ML;Alsaleh N;El-Kadi AO;Zeldin DC;Seubert JM
• 通讯作者: Seubert JM

The nuclear receptors constitutive active/androstane receptor and pregnane x receptor activate the Cyp2c55 gene in mouse liver.

核受体组成型活性/雄甾烷受体和孕烷x受体激活小鼠肝脏中的Cyp2c55基因。

• DOI: 10.1124/dmd.110.032334
• 发表时间: 2010
• 期刊: Drug metabolism and disposition: the biological fate of chemicals
• 作者: Konno,Yoshihiro;Kamino,Hiroki;Moore,Rick;Lih,Fred;Tomer,KennethB;Zeldin,DarrylC;Goldstein,JoyceA;Negishi,Masahiko
• 通讯作者: Negishi,Masahiko

Intimal smooth muscle cells are a source but not a sensor of anti-inflammatory CYP450 derived oxylipins.

内膜平滑肌细胞是抗炎 CYP450 衍生的氧脂质的来源，但不是传感器。

• DOI: 10.1016/j.bbrc.2015.06.012
• 发表时间: 2015
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Thomson,Scott;Edin,MatthewL;Lih,FredB;Davies,Michael;Yaqoob,MuhammadM;Hammock,BruceD;Gilroy,Derek;Zeldin,DarrylC;Bishop-Bailey,David
• 通讯作者: Bishop-Bailey,David

Increased CYP2J3 expression reduces insulin resistance in fructose-treated rats and db/db mice.

CYP2J3 表达增加可降低果糖治疗大鼠和 db/db 小鼠的胰岛素抵抗

• DOI: 10.2337/db09-1241
• 发表时间: 2010-04
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Xu X;Zhao CX;Wang L;Tu L;Fang X;Zheng C;Edin ML;Zeldin DC;Wang DW
• 通讯作者: Wang DW

Rosuvastatin attenuates the elevation in blood pressure induced by overexpression of human C-reactive protein.

• DOI: 10.1038/hr.2011.44
• 发表时间: 2011-07
• 期刊: HYPERTENSION RESEARCH
• 影响因子: 5.4
• 作者: Li, Xuguang;Yang, Guangtian;Zhao, Gang;Wu, Bin;Edin, Matthew L.;Zeldin, Darryl C.;Wang, Dao Wen
• 通讯作者: Wang, Dao Wen