Role of protein-S-glutathionylation in endothelial dysfunction and atherosclerosis
蛋白质-S-谷胱甘肽化在内皮功能障碍和动脉粥样硬化中的作用
基本信息
- 批准号:10331013
- 负责人:
- 金额:$ 41.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-04 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylcholineAdultAffectAmericanApolipoprotein EAtherosclerosisAttenuatedBiogenesisBiological AvailabilityBlood VesselsCRISPR/Cas technologyCardiovascular DiseasesCardiovascular systemCause of DeathCell physiologyCysteineDataDevelopmentDietDietary InterventionDown-RegulationEndothelial CellsEndotheliumEnzymesEquilibriumEventFunctional disorderGatekeepingGenerationsGrx1 proteinHemostatic functionHomeostasisHumanImpairmentInterventionKnock-outKnockout MiceLeadMeasuresMediatingMolecularMonitorMusMyocardial InfarctionNADPH OxidaseNitric OxideOxidasesOxidation-ReductionOxidative StressPathogenicityPathway interactionsPharmacologyPhysiologicalPopulationPost-Translational Protein ProcessingProductionProteinsPublishingReactive Oxygen SpeciesRecombinant ProteinsReportingResistanceRisk FactorsRoleSignal TransductionStimulusStrokeSystemTestingTimeTransgenesTransgenic MiceTransgenic OrganismsUbiquitinUnited StatesVascular DiseasesVascular EndotheliumVasodilationadenoviral-mediatedantioxidant enzymeatherogenesisatherosclerosis riskclinically relevantcombatdriving forceendothelial dysfunctionfemoral arteryhuman subjectimaging approachimprovedin vivomouse modelmulticatalytic endopeptidase complexmutantnovelnovel strategiesnovel therapeutic interventionoverexpressionpreservationrac1 GTP-Binding Proteinresponsesuccesstherapeutic targettherapeutically effectivetransgene expressionvascular endothelial dysfunctionvascular injurywestern diet
项目摘要
Project Summary
The path to atherosclerosis (AS) starts with vascular endothelial dysfunction (ED), which can be reversed;
however, effective therapeutic strategies targeting ED are still lacking. Small RhoGTPase Rac1, an established
master regulator of endothelial function, is integral to vascular homeostasis, governing vascular integrity and the
nitric oxide (NO) biogenesis system, but aberrant Rac1 signaling, in particular, Rac1-triggered NADPH-oxidase
(Nox)/reactive oxygen species (ROS) generation, has been strongly implicated in vascular oxidative stress and
AS and may therefore be a promising target for CVD treatment. However, to be successful at determining new
specific approaches to normalizing Rac1 signaling that can combat vascular oxidative stress to reverse ED and
AS, we must have a deep understanding of regulatory mechanisms of Rac1 to be able to balance Rac1's critical
functions with its proatherogenic consequences in endothelial cells (ECs). In this proposal, we will test whether:
(1) S-glutathionylation (PrS-SG), a stable but reversible oxidative post-translational modification, on cysteine
residues of Rac1 is a promising redox target, and (2) glutaredoxin-1 (Grx1), a prominent de-glutathionylation
enzyme, can preserve redox status and normal signaling of Rac1. We and others reported that activity and
stability of Rac1 are redox-sensitive and susceptible to PrS-SG. Our new preliminary data show that in both
human aortic ECs (HAECs) and aortae from a mouse model of AS, Rac1 underwent PrS-SG and degradation
in parallel with Grx1 downregulation; increasing Grx1 in HAECs preserved Rac1 redox status/expression.
Increasing endothelial Grx1 in mice attenuated diet-induced ED and AS. We thus hypothesize that during AS,
induction of PrS-SG on Rac1 promotes ED and AS, which can be reversed by replenishing Grx1 in endothelium.
We will test three aims: (1) Characterize in vivo role of endothelial Rac1/Grx1 axis in ED and AS; (2) Elucidate
the molecular mechanism of how PrS-SG on Rac1 drives ED; and (3) Test the potential of Rac1/Grx1 axis as a
therapeutic target in reversing ED and AS. To define the relationship between redox status/expression/activity
of Rac1/Grx1 and onset/progression of ED and AS (Aim 1), we will use EC-specific Grx1 transgenic and knockout
mice, as well as pharmacological inhibition of Rac1. To test if PrS-SG on Rac1 has a causal role in ED (Aim 2),
we will determine effects of expression of Rac1-SSG-mimic and -resistant mutants in generated Rac1-/- HAECs
on Nox/ROS signaling, eNOS dysfunction, and hyperpermeability. To test whether replenishing endothelial Grx1
can reverse vascular dysfunction and slow AS progression (Aim 3), we will use inducible EC-Grx1 transgenic
mice and ECs freshly isolated from human subjects with established AS. Success of this proposal is expected
to establish a novel redox mechanism that can specifically mediate Rac1 proatherogenic signaling, and provide
proof-of-concept that Grx1 can be used as a new therapeutic strategy for reversal of cardiovascular dysfunction.
项目摘要
动脉粥样硬化(AS)的发生始于血管内皮功能障碍(艾德),这种障碍是可以逆转的;
然而,针对艾德的有效治疗策略仍然缺乏。小RhoGTdR Rac 1,一种已建立的
内皮功能的主要调节因子,是血管内稳态的组成部分,控制血管完整性和
一氧化氮(NO)生物合成系统,但Rac 1信号异常,特别是Rac 1触发的NADPH氧化酶
(Nox)/活性氧(ROS)的产生,已强烈涉及血管氧化应激,
AS,因此可能是CVD治疗的一个有前途的目标。然而,为了成功地确定新的
使Rac 1信号正常化的特定方法,其可以对抗血管氧化应激以逆转艾德,
因此,我们必须深入了解Rac 1的调控机制,才能平衡Rac 1的关键作用,
在内皮细胞(EC)中起致动脉粥样硬化作用。在本提案中,我们将测试:
(1)S-谷胱甘肽化(PrS-SG),一种稳定但可逆的半胱氨酸氧化翻译后修饰
Rac 1的残基是一个有前途的氧化还原靶点,(2)谷氧还蛋白-1(Grx 1),一个突出的去谷胱甘肽化
酶,可以保持Rac 1的氧化还原状态和正常信号传导。我们和其他人报告说,
Rac 1的稳定性对氧化还原敏感且对PrS-SG敏感。我们新的初步数据显示,
人主动脉内皮细胞(HAECs)和来自AS小鼠模型的内皮细胞,Rac 1经历PrS-SG和降解
与Grx 1下调平行;增加HAECs中Grx 1保留Rac 1氧化还原状态/表达。
增加小鼠内皮细胞Grx 1可减弱饮食诱导的艾德和AS。因此,我们假设在AS期间,
PrS-SG对Rac 1诱导可促进艾德和AS,补充内皮Grx 1可逆转这一作用。
我们将测试三个目标:(1)表征内皮细胞Rac 1/Grx 1轴在艾德和AS中的体内作用;(2)阐明内皮细胞Rac 1/Grx 1轴在AS中的作用。
Rac 1上的PrS-SG如何驱动艾德的分子机制;和(3)测试Rac 1/Grx 1轴作为一个驱动力的潜力。
逆转艾德和AS的治疗靶点。定义氧化还原状态/表达/活性之间的关系
Rac 1/Grx 1与艾德和AS发病/进展的关系(目的1),我们将使用EC特异性Grx 1转基因和敲除
小鼠,以及Rac 1的药理学抑制。为了测试Rac 1上的PrS-SG是否在艾德中具有因果作用(目的2),
我们将确定Rac 1-SSG模拟物和抗性突变体在产生的Rac 1-/- HAECs中的表达效果
对Nox/ROS信号传导、eNOS功能障碍和高通透性的影响。为了检测补充内皮细胞Grx 1
可以逆转血管功能障碍和减缓AS进展(目的3),我们将使用诱导型EC-Grx 1转基因
小鼠和从患有AS的人类受试者新鲜分离的EC。预计这一提议将获得成功
建立一种新的氧化还原机制,可以特异性介导Rac 1促动脉粥样硬化信号传导,并提供
概念验证表明Grx 1可用作逆转心血管功能障碍的新治疗策略。
项目成果
期刊论文数量(0)
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JINGYAN HAN其他文献
JINGYAN HAN的其他文献
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{{ truncateString('JINGYAN HAN', 18)}}的其他基金
Role of protein-S-glutathionylation in endothelial dysfunction and atherosclerosis
蛋白质-S-谷胱甘肽化在内皮功能障碍和动脉粥样硬化中的作用
- 批准号:
9883986 - 财政年份:2020
- 资助金额:
$ 41.25万 - 项目类别:
Role of protein-S-glutathionylation in endothelial dysfunction and atherosclerosis
蛋白质-S-谷胱甘肽化在内皮功能障碍和动脉粥样硬化中的作用
- 批准号:
10551314 - 财政年份:2020
- 资助金额:
$ 41.25万 - 项目类别:
Protein S-glutathionylation and vascular dysfunction with aging
衰老过程中蛋白质 S-谷胱甘肽化和血管功能障碍
- 批准号:
9751680 - 财政年份:2018
- 资助金额:
$ 41.25万 - 项目类别:
Role of protein-S-glutathionylation in endothelial dysfunction and atherosclerosis
蛋白质-S-谷胱甘肽化在内皮功能障碍和动脉粥样硬化中的作用
- 批准号:
9544365 - 财政年份:2017
- 资助金额:
$ 41.25万 - 项目类别:
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