Role of Cyp2j-epoxygenases, sEH and PPARs in adenosine-induced vascular response

Cyp2j-环氧合酶、sEH 和 PPAR 在腺苷诱导的血管反应中的作用

基本信息

批准号：
9185998
负责人：
Mohammed A Nayeem
金额：
$ 37.55万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9185998
关键词：
ADORA2A gene Acetylcholine Adenosine Adenosine A1 Receptor Adenylate Cyclase Affect Agonist Anti-Inflammatory Agents Anti-inflammatory Aorta Bathing Blood Pressure Blood Vessels Cardiovascular Diseases Cell Line Cell physiology Clinical Coronary artery Country Coupling Cyclic AMP-Dependent Protein Kinases Data Development Down-Regulation Drug Design Endothelial Cells Endothelium Epoxide hydrolase Exercise Exhibits Experimental Designs G-substrate GTP-Binding Proteins Genes Genetic Polymorphism Goals Human Hypertension Individual Kidney Link Measures Mediating Mitogen-Activated Protein Kinase Inhibitor Mus Myocardial perfusion Organ Outcome PKA inhibitor PPAR Pathway Patients Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Pharmacology Population Prevention Publishing Purinergic P1 Receptors Receptor Gene Relaxation Reporting Research Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Smooth Muscle Myocytes Technology Testing Therapeutic Uses Transgenic Mice Vascular Endothelium Vasodilation Western Blotting Wild Type Mouse base blood pressure regulation drinking water endothelial dysfunction genetic variant inhibitor/antagonist innovation knockout gene mRNA Expression new therapeutic target novel overexpression perfusion imaging protein expression public health relevance renal artery response tool vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Endothelial dysfunction is associated with corresponding changes in vascular tone and increases in contractility, a condition that may cause hypertension in susceptible individuals which may have allelic variants in cyp2j-epoxygenases, soluble epoxide hydrolase (sEH), A2A, and A1 adenosine receptors (A2A AR & A1 AR) genes. These allelic variants may have similarities to our transgenic mice which may regulate vascular tone and blood pressure (BP). Our preliminary data have suggested a possible link between adenosine-induced relaxation and opening of KATP channels through A2A AR-cyp2j-PKA-PPAR? pathway. Also, it is possible that a link may exist between adenosine-induced contraction and closing of KATP channels through A1 AR-sEH-cyp4a- PPAR� pathway. A combination of pharmacological tools and transgenic mice would allow us to identify the possible targets as a long term goal to treat population which may have allelic variants leading to hypertension. Therefore, there is a critical need to explore the possible mechanism involving cyp2j2-epoxygenases, sEH/cyp4a, A1 AR/A2A AR, PPAR�/?, PKA/PKC�/� and KATP channels in adenosine-induced vascular responses. Our central hypothesis is that adenosine induces vascular relaxation and decreases in BP through cyp2j-epoxygenases via A2A AR-cyp2j-PKA-PPAR? signaling leading to opening of KATP channels. On the other hand, adenosine induces vascular contraction and increases in BP through sEH via A1 AR-sEH-cyp4a-PPAR� pathway leading to closing of KATP channels. To test this hypothesis, we propose to explore in depth mechanism(s) using A2A AR-/-, A1 AR-/-, cyp2j5-/-, sEH-/-, Tie2-cyp2j2Tr (endothelial-cyp2j2 overexpressed), Tie2-sEHTr (endothelial-sEH overexpressed), wild-type mice, immortal renal endothelial cell line from H-2Kb- tsA58 mouse, mouse aortic endothelial cells (MAEC) and mouse aortic smooth muscle cells (MASMC). Further, we will also explore the possible treatment with sEH inhibitors (AUDA/t-AUCB) in drinking water (or gavage) for A2A AR-/-, cyp2j5-/- and Tie2-sEHTr mice which may have high BP. We will measure BP, and we will use aortas/renal arteries (organ bath/DMT-wire myograph) with treatments (adenosine-receptors agonists & antagonists), cyp-epoxygenases, sEH, adenylyl cyclase, PKC�/�/, MAPK and PKA inhibitors, PPAR�/?, EETs and KATP channel (activators & inhibitors). EETs & DHETs will be analyzed (UPLC-MS/MS). Western blot & RT-PCR will be used for proteins & mRNA expression. We propose 3 specific aims to determine: (1) whether the cyp2j-epxygenases or sEH affects BP, adenosine-induced vascular response and EETs/DHETs; (2) whether the presence or absence of A2A AR affects adenosine-induced vascular response through PPARs via cyp2j-epoxygenases, sEH (3) whether the presence /overexpression of cyp2j-epoxygenases or sEH regulate KATP channels through A2A AR-cyp2j-PKA-PPAR?/A1 AR-sEH-cyp4a-PPAR� pathway in adenosine-induced vascular response. Such results can have a positive impact, as the identified components are expected to provide new targets to curb clinical problems linked with dysfunctional endothelium leading to hypertension.

描述（由申请人提供）：带有Corresspond的血管张力变化和Y的增加的entherer功能障碍，这种情况可能会在cyphe-epoxygenasses ASE（SEH），A2A和A1腺苷受体（A2A（A2A）中具有等位基因变异的敏感个体的疾病（A2A）（A2A）（A2A） AR和A1 AR基因。这些等位基因变异可能与我们的转基因小鼠相似CYP2J-PKA-PPAR？需要探索涉及涉及CYP2J2-氧化酶的机制，SEH/CYP4A，A1 AR/A2A AR，PPAR/？另一方家，TIE2-CYP2J2TR（内皮CYP2J2过表达）E2-SEHTR（内皮 - SEH过表达），野生型小鼠，来自H-2KB-TSA58小鼠主动脉主动脉内皮细胞（MAEC）主动脉平滑肌细胞（MASMASC）的H-2KB-TSA58小鼠主动脉内皮细胞（MASMASMC）的不朽肾细胞系。此外，我们还将在饮用水中使用SEH抑制剂（AUDA/T-AUCB）进行A2A AR - / - / - 和TIE2-SEHTR小鼠的饮用水（或gavage）。器官浴/dmt-wire mygraph）带有处理（腺苷 - 受体激动剂和拮抗剂），cyp--氧化酶，SEH，腺苷酸环化酶，PKC。）。通过CYP2J-氧化酶 - 氧化酶或SEH法定的KATP通道，他CYP2J-PKA-PPAR？/a1 ar-seh-cyp4a-a-ppar可以带来积极的影响。与功能失调的内皮有关导致高血压的临床问题。