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(SMCs)中大量表达。
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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