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Angiotensin-II, GTPCH1 and 26S Protesomes

血管紧张素-II、GTPCH1 和 26S 蛋白酶体

基本信息

批准号：
8494677
负责人：
MING-HUI ZOU
金额：
$ 34.52万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8494677
关键词：
26S proteasome Acetates Angiotensin II Animal Model Animals Arginine Atherosclerosis Biological Availability Biology Biopterin Blood Pressure Blood Vessels Blood flow Brain Cardiovascular Diseases Caspase Cells Clip Complex Coupled Cultured Cells Cysteine DNA Sequence Rearrangement Data Deoxycorticosterone Development Diabetes Mellitus Disease Electrons Endothelial Cells Endothelium Enzymes Equilibrium Experimental Animal Model FDA approved Forearm Free Radicals Functional disorder GTP Cyclohydrolase I Gene Silencing Goals Goldblatt Syndrome Guanosine Guanosine Triphosphate Health Human Hydrogen Peroxide Hydroxylation Hypertension Hypotension Individual Injury Kidney Knock-out Knowledge Lead Link MG132 Maintenance Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Modality Modeling Modification Molecular Mus Muscle Tonus NADP NADPH Oxidase Nitric Oxide Oxidants Oxidases Oxidative Stress Oxygen PA700 proteasome activator Pathway interactions Patients Peptide Mapping Peroxonitrite Phenylalanine Hydroxylase Post-Translational Protein Processing Production Proteasome Inhibition Proteasome Inhibitor Proteins Reactive Nitrogen Species Reactive Oxygen Species Regimen Regulation Role Sepiapterin reductase Signal Pathway Signal Transduction Sodium Chloride Stimulus Superoxide Dismutase Superoxides Supplementation System Testing Therapeutic Therapeutic Effect Tissues Transgenic Mice Transgenic Organisms Trypsin Tryptophan 5-monooxygenase Tyrosine Tyrosine 3-Monooxygenase Ubiquitin Ubiquitin-Activating Enzymes Ubiquitin-Conjugating Enzymes Ubiquitination Vascular Diseases Vascular Endothelial Cell Vascular System blood pressure regulation cancer therapy cardiovascular risk factor chymotrypsin cofactor diabetic enzyme activity exposed human population human NOS3 protein improved in vitro Model in vivo insight mRNA Expression mouse model multicatalytic endopeptidase complex mutant nitration overexpression oxidation prevent protein expression sepiapterin tetrahydrobiopterin therapeutic target tripolyphosphate ubiquitin-protein ligase vascular endothelial dysfunction

项目摘要

DESCRIPTION (provided by applicant): Guanosine 5'-triphosphate cyclohydrolase I (GTPCH1) is a homodecameric protein consisting of 25-kDa subunits, which enzyme catalyzes the rearrangement of GTP to dihydroneopterin triphosphate, a species subsequently converted to tetrahydrobiopterins (BH4) through the sequential action of 6-pyruvoyltetrahydrobiopterin synthase and sepiapterin reductase. In contrast to the latter two enzymes, GTPCH1 is the rate-limiting enzyme in most tissues, making it the major determinant of intracellular BH4 content. GTPCH1 is constitutively expressed in vascular cells; however, whether GTPCH1 is critical for the maintenance of BH4 levels in these cells is unknown. Several recent studies suggest that BH4 deficiency is responsible for endothelial nitric oxide synthase (eNOS) uncoupling during hypertension, as seen by the finding that hypertension and related eNOS uncoupling are effectively prevented by co- administration of sepiapterin, a precursor for BH4. BH4 supplementation or increased BH4 synthesis by GTPCH1 restores BH4 levels and normalizes eNOS function in the deoxycorticosterone acetate (DOCA)-salt hypertensive mice. GTPCH1 activity, as well as BH4 levels, is reduced in these mice. However, the in vivo cause-effect relationship between eNOS uncoupling and GTPCH1, which is critical for eNOS-mediated protection of endothelial function, has yet to be investigated. In particular, it is unclear how pathological stimuli such as hypertension reduce GTPCH1 levels and how stimuli such as angiotensin-II (Ang II) and hypertension modulate proteasome function. Our exciting new preliminary data have led us to hypothesize that Ang II, via oxidants such as ONOO-, increases 26S proteasome-mediated degradation of GTPCH1, resulting in BH4 deficiency, eNOS uncoupling, and the elevation of blood pressure. This central hypothesis will be tested in three interrelated specific aims by using a combination of experimental approaches including purified proteins, cultured cells, and several models of hypertension in vivo. The proposed studies are significant, as they will deepen our understanding of the upstream regulation of BH4 levels, the contribution of oxidative stress and ubiquitin-proteasome systems in the development of vascular injury, and the contribution of oxidative stress in blood pressure regulation. In particular, these studies will provide clues as to the therapeutic effects of MG132, a proteasome inhibitor that was recently approved by the FDA for cancer therapy.

描述（由申请人提供）：鸟苷5'-三磷酸环水解酶I （GTPCH1）是一种由25 kda亚基组成的同十聚体蛋白，该酶催化GTP重排为三磷酸二氢蝶呤，随后通过6-丙酮酰基四氢蝶呤合成酶和七氢蝶呤还原酶的顺序作用转化为四氢生物蝶呤（BH4）。与后两种酶相反，GTPCH1在大多数组织中是限速酶，使其成为细胞内BH4含量的主要决定因素。GTPCH1在血管细胞中组成性表达；然而，GTPCH1是否对这些细胞中BH4水平的维持至关重要尚不清楚。最近的一些研究表明BH4缺乏是高血压期间内皮型一氧化氮合酶（eNOS）解偶联的原因，正如发现高血压和相关的eNOS解偶联可以通过联合给药sepapterin （BH4的前体）有效预防。补充BH4或通过GTPCH1增加BH4合成可恢复BH4水平，使醋酸脱氧皮质酮盐高血压小鼠eNOS功能正常化。GTPCH1活性以及BH4水平在这些小鼠中降低。然而，eNOS解耦与GTPCH1之间的体内因果关系尚未研究，GTPCH1对eNOS介导的内皮功能保护至关重要。特别是，目前尚不清楚高血压等病理性刺激如何降低GTPCH1水平，以及血管紧张素-II （Ang II）和高血压等刺激如何调节蛋白酶体功能。我们令人兴奋的新初步数据使我们假设Ang II通过氧化剂（如ONOO-）增加26S蛋白酶体介导的GTPCH1降解，导致BH4缺乏，eNOS解偶联和血压升高。这一中心假设将在三个相互关联的特定目标中进行测试，通过使用实验方法的组合，包括纯化蛋白、培养细胞和几种体内高血压模型。这些研究将加深我们对BH4水平的上游调控、氧化应激和泛素-蛋白酶体系统在血管损伤发展中的作用以及氧化应激在血压调节中的作用的理解，具有重要意义。特别是，这些研究将为MG132的治疗效果提供线索，MG132是一种蛋白酶体抑制剂，最近被FDA批准用于癌症治疗。