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.

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.

项目成果

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

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

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

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

The epoxygenases CYP2J2 activates the nuclear receptor PPARalpha in vitro and in vivo.

• DOI: 10.1371/journal.pone.0007421
• 发表时间: 2009-10-12
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wray JA;Sugden MC;Zeldin DC;Greenwood GK;Samsuddin S;Miller-Degraff L;Bradbury JA;Holness MJ;Warner TD;Bishop-Bailey D
• 通讯作者: Bishop-Bailey D