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 将花生四烯酸 (AA) 代谢为环氧二十碳三烯酸 (EET)，对心血管和肾功能具有有效影响。 EET 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)。 目前的研究包括：（1）CYP2J和CYP2C亚家族P450在生化和分子水平上的表征； (2)评价CYP2J产物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) 在选定的人类疾病动物模型（缺血性心脏病、高血压、动脉粥样硬化、癌症）中检查该通路，以及 (5) 评估人类 CYP2C、CYP2J、sEH 和 mEH 基因多态性对心血管功能的影响和疾病。尽管我们将大部分精力集中在人类 CYP2J2 和小鼠 CYP2J5 上，但我们已经发现了许多哺乳动物 CYP2J。人CYP2J2是在心脏和脉管系统中表达的主要人P450，其定位于心肌细胞和内皮细胞，并且在AA到EET的代谢中活跃。 CYP2J2衍生的EETs是血管扩张剂，抑制细胞因子诱导的内皮细胞粘附分子表达，诱导组织纤溶酶原激活剂基因表达，抑制血管平滑肌细胞迁移，保护内皮细胞免受缺氧-复氧损伤和凋亡，上调内皮一氧化氮生物合成，影响心脏电生理学，保护心脏免受缺血性损伤。 CYP2J2 转基因小鼠（α-肌球蛋白重链启动子驱动心脏特异性表达）被开发用于研究 EET 增加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，改善了缺血后左心室功能，缩短了心脏动作电位，改变了心脏电生理学，并增强了β-肾上腺素能受体反应性。类似地，表现出 EET 水解减少的 sEH 缺失小鼠改善了缺血后功能恢复。我们发现 mEH 在体内调节 EET 水平，并且 mEH/sEH 双缺失小鼠的心脏相对于 sEH 缺失小鼠的心脏具有更好的心脏功能恢复。我们还开发了转基因小鼠，其中 CYP2J2、CYP2C8 或 sEH 仅在内皮细胞中表达（Tie2 启动子驱动），以检查这些酶及其产物对血管功能的作用。 CYP 或 sEH 的内皮表达调节血管生成，从而促进肿瘤形成和生长并调节视网膜血管化。人类 CYP2J2 基因已被克隆、测序和表征。我们已经确定了几种功能相关的 CYP2J2 多态性变异，其中一种与 CYP2J2 表达降低相关，并且与几个队列中的心血管疾病风险相关。我们还鉴定了 sEH 基因中功能相关的多态性，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 是一种主要的小鼠 P450 花生四烯酸环氧化酶，在肾脏中表达并定位于近端肾小管。 CYP2J5缺失小鼠患有自发性高血压，在高盐和低盐饮食下均持续存在。与这些发现一致的是，我们在田纳西州的一个队列中证明了 CYP2J2 多态性变异与高血压之间存在关联。鉴于 sEH 抑制剂 (sEHis) 的抗炎作用，我们研究了 sEHis 在减弱 SARS-CoV-2 诱导的类二十烷酸和细胞因子风暴中的作用。 该项目涉及人类冠状病毒、新型冠状病毒、COVID-19、严重急性呼吸系统综合症冠状病毒病、SARS冠状病毒、SARS-coronavirus-2、SARS-cov-2、SARS-cov2、SARS相关冠状病毒2、严重急性呼吸道疾病的研究综合征冠状病毒 2、SARS 相关冠状病毒、SARS-cov 或 SARS 相关冠状病毒。

项目成果

Overexpression of CYP2J2 provides protection against doxorubicin-induced cardiotoxicity.

CYP2J2 的过度表达可针对阿霉素诱导的心脏毒性提供保护。

• DOI: 10.1152/ajpheart.00983.2008
• 发表时间: 2009-07-01
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: Yun;H. El;K. Chaudhary;S. Batchu;A. Shayeganpour;Taibeh Orujy Jukar;J. Bradbury;Joan P. Graves;L. Degraff;P. Myers;D. C. Rouse;J. Foley;A. Nyska;D. Zeldin;J. Seubert
• 通讯作者: J. Seubert

CYP2J2 overexpression ameliorates hyperlipidemia via increased fatty acid oxidation mediated by the AMPK pathway.

CYP2J2 过表达通过 AMPK 途径介导的脂肪酸氧化增加来改善高脂血症。

• 发表时间: 2015-07
• 作者: Zhang, Shasha;Chen, Guangzhi;Li, Ning;Dai, Meiyan;Chen, Chen;Wang, Peihua;Tang, Huiru;Hoopes, Samantha L;Zeldin, Darryl C;Wang, Dao Wen;Xu, Xizhen
• 通讯作者: Xu, Xizhen

An improved protocol for the treatment of fulminant myocarditis.

治疗暴发性心肌炎的改进方案。

• 发表时间: 2019
• 作者: Edin, Matthew L;Zeldin, Darryl C
• 通讯作者: Zeldin, Darryl C

Author Correction: Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment.

作者更正：环氧二十碳三烯酸增强胚胎造血和成体骨髓植入。

• 发表时间: 2019-09
• 影响因子: 64.8
• 作者: Li, Pulin;Lahvic, Jamie L;Binder, Vera;Pugach, Emily K;Riley, Elizabeth B;Tamplin, Owen J;Panigrahy, Dipak;Bowman, Teresa V;Barrett, Francesca G;Heffner, Garrett C;McKinney;Schlaeger, Thorsten M;Daley, George Q;Zeldin, Darryl
• 通讯作者: Zeldin, Darryl

Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin.

分析阿司匹林抗血栓和促血栓形成作用背后的类二十烷酸网络。

• 发表时间: 2020
• 作者: Crescente, Marilena;Armstrong, Paul C;Kirkby, Nicholas S;Edin, Matthew L;Chan, Melissa V;Lih, Fred B;Jiao, Jing;Maffucci, Tania;Allan, Harriet E;Mein, Charles A;Gaston;Cottrell, Graeme S;Mitchell, Jane A;Zeldin, Darryl C;Hers
• 通讯作者: Hers