Anti-Atherogenic Mechanisms of Drebrin
Drebrin 的抗动脉粥样硬化机制
基本信息
- 批准号:10532356
- 负责人:
- 金额:$ 52.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-12-16 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:Actin-Binding ProteinAngiotensin IIAntiatherogenicAortaApolipoprotein EArterial Fatty StreakArterial InjuryArteriesAtherosclerosisCX3CL1 geneCarotid ArteriesCd68Cell LineageCell ProliferationCellsCholesterolCommon carotid arteryCongestive Heart FailureDevelopmentDiseaseDown-RegulationDynaminEndocytosisEndocytosis InhibitionEnzymesExhibitsFoam CellsFractalkineGKLF proteinGenerationsGenesGlutathione Metabolism PathwayGlutathione S-TransferaseGoalsHumanIn VitroInflammatoryKnock-inKnowledgeLoxP-flanked alleleMacrophageMass Spectrum AnalysisMediatingMedicalMemoryMicrofilamentsMissionMolecularMorbidity - disease rateMusMyocardial InfarctionNADPH Oxidase 1NeuronsNuclearNuclear TranslocationPhagocytesPhenotypePrevalenceProcessProductionProteinsPublic HealthReactive Oxygen SpeciesResearchRoleSignal TransductionSmooth Muscle MyocytesStrokeTestingUnited States National Institutes of HealthVascular Smooth Muscleascending aortaatherogenesisburden of illnesscell motilitycongeniccytokinedisabilitydrebrinsin vivomortalitynovel therapeutic interventionoxidized low density lipoproteinresponsetranscription factortransdifferentiationvascular inflammationvascular injurywestern diet
项目摘要
We discovered that the actin-binding protein, Drebrin, is abundantly expressed in smooth muscle cells (SMCs)
and is up-regulated in response to arterial injury in mice and to atherosclerosis in humans. Comparing WT
with Dbn-/+ mice, we found that Drebrin inhibits SMC migration and proliferation, both in vitro and in vivo,
through stabilization of actin filaments. In studies with SMC-specific Dbn-/- (SMC-Dbn-/-) mice, we found that
SMC Drebrin limits angiotensin II-induced remodeling of the ascending aorta, in a manner that correlates with
down-regulation of NADPH oxidase 1 (NOX1), decreased SMC reactive oxygen species (ROS) production and
reduced vascular inflammation. Thus, Drebrin constrains not only the migratory/proliferative SMC phenotype
but also the pro-inflammatory SMC phenotype evoked by vascular injury and angiotensin II. Congruently, we
found that atherosclerosis is greater in SMC-Dbn-/-/Ldlr-/- than in congenic SMC-Dbn+/+/Ldlr-/- mice. Because
SMC Drebrin negatively regulates atherosclerosis, our goals are to determine the mechanisms by which
Drebrin regulates SMC pro-inflammatory signaling and whether enhanced SMC expression of Drebrin can
inhibit atherogenesis. To this end, we performed SILAC/mass spectrometry studies on Dbn-/- and congenic
WT SMCs. We found that whereas in Dbn-/- SMCs the ROS-defensive enzyme Glutathione-S-transferase µ1
(GSTM1) is down-regulated, the pro-inflammatory cytokine CX3CL1 (fractalkine) is up-regulated: thus we will
investigate the role of these proteins in mediating the phenotype of Dbn-/- SMCs. Because endocytosis of
NOX1 regulates ROS generation and activation of pro-inflammatory NFκB signaling and Drebrin has been
shown to inhibit endocytosis, we will investigate whether Drebrin inhibits NOX1-mediated ROS generation by
inhibiting endocytosis. A major focus of our studies will be pro-atherogenic SMC-derived foam cells, which
SMC lineage tracing studies have shown, comprise ~40% of foam cells in atherosclerotic lesions. Our
Preliminary Studies show that, compared with cognate Dbnflox/flox SMCs, Dbn-/- SMCs induced to
transdifferentiate with cholesterol loading exhibited increased expression of the macrophage marker, CD68,
and Kruppel-like factor 4 (KLF4), a transcription factor required for SMC-to-foam cell transdifferentiation. By
grafting common carotid arteries from Dbnflox/flox and SMC-Dbn-/- mice into carotid arteries of congenic Apoe-/-
mice, we also show that Drebrin deficiency augments transdifferentiation of SMCs to CD68+ cells in vivo. We
will test the hypothesis that Drebrin inhibits atherogenesis by limiting SMC transdifferentiation into foam cells.
To do so, we will establish whether Drebrin inhibits SMC-to-foam cell transdifferentiation and associated pro-
inflammatory signaling, both in vitro and in vivo; determine if Drebrin inhibits SMC transdifferentiation through
ROS-dependent mechanisms; and define the roles of GSTM1 and CX3CL1 in mediating Drebrin’s inhibitory
effects on SMC transdifferentiation and pro-inflammatory signaling.
我们发现肌动蛋白结合蛋白Drebrin在平滑肌细胞(SMC)中大量表达。
在小鼠的动脉损伤和人类的动脉粥样硬化中表达上调。比较WT
在DBN-/+小鼠身上,我们发现Drebrin在体外和体内都抑制了SMC的迁移和增殖,
通过稳定肌动蛋白细丝。在对SMC特异性DBN-/-(SMC-DBN-/-)小鼠的研究中,我们发现
SMC Drebrin抑制血管紧张素II诱导的升主动脉重塑,其方式与
下调NADPH氧化酶1(NOX1),减少SMC活性氧自由基(ROS)的产生,并
减少血管炎症。因此,Drebrin不仅抑制迁移/增殖的SMC表型
也包括由血管损伤和血管紧张素II引起的促炎性SMC表型。
发现SMC-DBN-/-/Ldlr-/-小鼠的动脉粥样硬化程度比同基因SMC-DBN+/+/Ldlr-/-小鼠更严重。因为
SMC Drebrin负性调节动脉粥样硬化,我们的目标是确定其机制
Drebrin调节SMC促炎信号及增强SMC表达是否可以
抑制动脉粥样硬化形成。为此,我们对DBN-/-和同源基因进行了SILAC/MS研究
WT SMCs。我们发现,在DBN-/-SMC中,ROS防御酶谷胱甘肽-S-转移酶µ1
(GSTM1)下调,促炎症细胞因子CX3CL1(Fractalkine)上调:因此,我们将
研究这些蛋白在介导DBN-/-SMC表型中的作用。因为细菌的内吞作用
NOX1调节ROS的产生和激活促炎症的NFκB信号和Drebrin已被
我们将研究Drebrin是否通过以下方式抑制NOX1介导的ROS的产生
抑制内吞作用。我们研究的一个主要焦点将是促动脉粥样硬化的SMC来源的泡沫细胞,它
SMC谱系追踪研究表明,在动脉粥样硬化病变中,SMC约占泡沫细胞的40%。我们的
初步研究表明,与同源Dbnflx/FLOX SMC相比,DBN-/-SMC诱导
随着胆固醇负荷的增加,巨噬细胞标志物CD68的表达增加,
Kruppel样因子4(KLF4),SMC向泡沫细胞转分化所需的转录因子。通过
Dbnflx/Flox和SMC-DBN-/-小鼠颈总动脉移植到同种APOE-/-的颈动脉
我们还发现,在体内,Drebrin缺乏会增强SMC向CD68+细胞的转分化。我们
将验证Drebrin通过限制SMC向泡沫细胞的转分化来抑制动脉粥样硬化形成的假设。
为此,我们将确定Drebrin是否抑制SMC到泡沫细胞的转分化和相关的促泡沫细胞分化。
体外和体内的炎症信号;确定Drebrin是否通过
ROS依赖的机制;并确定GSTM1和CX3CL1在介导Drebrin抑制中的作用
对SMC转分化和促炎信号的影响。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation.
- DOI:10.1093/cvr/cvab156
- 发表时间:2021-04
- 期刊:
- 影响因子:10.8
- 作者:Jiao‐Hui Wu;Lisheng Zhang;Igor Nepliouev;L. Brian;Taiqin Huang;Kamie P Snow;B. Schickling;E. Hauser;F. Miller;N. Freedman;Jonathan A Stiber
- 通讯作者:Jiao‐Hui Wu;Lisheng Zhang;Igor Nepliouev;L. Brian;Taiqin Huang;Kamie P Snow;B. Schickling;E. Hauser;F. Miller;N. Freedman;Jonathan A Stiber
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NEIL J. FREEDMAN其他文献
NEIL J. FREEDMAN的其他文献
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{{ truncateString('NEIL J. FREEDMAN', 18)}}的其他基金
Mechanisms by which Small Nucleolar RNAs Exacerbate Atherosclerosis
小核仁 RNA 加剧动脉粥样硬化的机制
- 批准号:
10502380 - 财政年份:2022
- 资助金额:
$ 52.33万 - 项目类别:
Mechanisms by which Small Nucleolar RNAs Exacerbate Atherosclerosis
小核仁 RNA 加剧动脉粥样硬化的机制
- 批准号:
10670399 - 财政年份:2022
- 资助金额:
$ 52.33万 - 项目类别:
Regulation of Vascular Inflammatory Signaling by the Deubiquitinase USP20
去泛素酶 USP20 对血管炎症信号的调节
- 批准号:
9765984 - 财政年份:2019
- 资助金额:
$ 52.33万 - 项目类别:
Regulation of Vascular Inflammatory Signaling by the Deubiquitinase USP20
去泛素酶 USP20 对血管炎症信号的调节
- 批准号:
9893026 - 财政年份:2019
- 资助金额:
$ 52.33万 - 项目类别:
Regulation of Vascular Inflammatory Signaling by the Deubiquitinase USP20
去泛素酶 USP20 对血管炎症信号的调节
- 批准号:
10349573 - 财政年份:2019
- 资助金额:
$ 52.33万 - 项目类别:
Regulation of Vascular Inflammatory Signaling by the Deubiquitinase USP20
去泛素酶 USP20 对血管炎症信号的调节
- 批准号:
10112295 - 财政年份:2019
- 资助金额:
$ 52.33万 - 项目类别:
Regulation of B-arrestin2's pro-atherogenic activity by the deubiquitinase USP20
去泛素酶 USP20 对 B-arrestin2 促动脉粥样硬化活性的调节
- 批准号:
8797106 - 财政年份:2014
- 资助金额:
$ 52.33万 - 项目类别:
Regulation of B-arrestin2's pro-atherogenic activity by the deubiquitinase USP20
去泛素酶 USP20 对 B-arrestin2 促动脉粥样硬化活性的调节
- 批准号:
8639259 - 财政年份:2014
- 资助金额:
$ 52.33万 - 项目类别:
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