miRNA-mediated reduction of VSMC foam cell formation
miRNA 介导的 VSMC 泡沫细胞形成减少
基本信息
- 批准号:10376766
- 负责人:
- 金额:$ 53.57万
- 依托单位:
- 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:2013-07-23 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:Adaptor Signaling ProteinAnti-Inflammatory AgentsAntiinflammatory EffectApoptosisArterial Fatty StreakArteriesAtherosclerosisAttenuatedBlood VesselsCarotid ArteriesCell CycleCellsCholesterolDataDevelopmentDiseaseDown-RegulationEventFoam CellsFunctional disorderFundingGoalsHomeostasisHyperlipidemiaImmunohistochemistryInflammatoryKnockout MiceLigationLinkLipidsLow Density Lipoprotein ReceptorLow-Density LipoproteinsMedialMediatingMicroRNAsModelingMolecularMusMuscleMutationPathway interactionsPatientsPharmacotherapyPhenotypeProcessPublishingRegulationReportingRoleSmall Interfering RNASmooth Muscle MyocytesStimulusSyndromeTestingTherapeuticVascular DiseasesVascular ProliferationVascular Smooth MuscleWorkatherogenesisatheroprotectivecell injurycell typeconditional knockoutcytokinehypercholesterolemiain vivointerleukin-19macrophagenoveloxidized low density lipoproteinprotein protein interactionreceptorresponserestenosistransdifferentiationuptakevascular smooth muscle cell proliferation
项目摘要
The transformation of vascular smooth muscle cells (VSMC) into foam cells leading to increased plaque
size and decreased stability is a key, yet understudied step in atherogenesis. Our work in the previous
funding cycle (HL117724) demonstrated that Interleukin-19 (IL-19), a novel, anti-inflammatory cytokine,
attenuates atherosclerosis by multiple anti-inflammatory effects on VSMC as well as by increasing lipid
uptake and efflux in macrophage. In published and preliminary studies described here, we show that IL-19
reduces lipid accumulation in VSMC, an atheroprotective event, but without modifying expression of lipid
receptors or transporters. IL-19 induces expression of miR133a, a muscle-specific miRNA previously
ascribed to regulate VSMC phenotype. Although unrecognized and unreported, we have identified that
miR133a can target and reduce expression of Low Density Lipoprotein Receptor Adaptor Protein 1,
(LDLRAP1), an adaptor protein which functions to internalize the LDL receptor. Patients with mutations in
LDLRAP1 have LDL receptor malfunction leading to hyperlipidemia and Autosomal Recessive
Hypercholesterolemia (ARH) disorder. Nothing at all is known about a role for miR133a in regulation of
lipid uptake and development of atherosclerosis. Similarly, nothing at all has been published about
LDLRAP1 expression, function, and participation in VSMC foam cell formation. We have reported that that
both miR133a and LDLRAP1 regulate oxLDL uptake in VSMC. LDLRAP1 is induced in VSMC by oxLDL, is
not detectible in normal medial VSMC, but is expressed in plaque and neointimal VSMC of injured arteries.
IL-19 can reduce LDLRAP1 expression and oxLDL uptake in VSMC. Both miR133a and LDLRAP1regulate
VSMC proliferation, previously unrecognized functions for these molecules. Preliminary studies indicate
that the LDLRAP1+/- mouse has increased atherosclerosis, but reduced restenosis. In this competitive
renewal application, we hypothesize that LDLRAP1 can be selectively reduced in VSMC because miR133a
is muscle specific, and that reduction of lipid uptake by VSMC is atheroprotective and could also attenuate
vascular proliferative syndromes. The overall goals of this application are to determine causative roles for
miR133a and LDLRAP1 in VSMC lipid uptake, proliferation, atherogenesis, cholesterol-induced phenotype
modulation, and vascular restenosis.
血管平滑肌细胞(VSMC)转化为泡沫细胞,导致斑块增加
尺寸和稳定性降低是动脉粥样硬化形成中的关键但未充分研究的步骤。我们在过去的工作
资助周期(HL 117724)证明白细胞介素-19(IL-19),一种新的抗炎细胞因子,
通过对VSMC的多种抗炎作用以及通过增加脂质
在巨噬细胞中的摄取和流出。在这里描述的已发表和初步研究中,我们表明IL-19
减少VSMC中的脂质积聚,这是一种动脉粥样硬化保护事件,但不改变脂质的表达
受体或转运蛋白。IL-19诱导miR 133 a的表达,miR 133 a是一种肌肉特异性miRNA,
调节VSMC表型。虽然没有得到承认和报告,我们已经确定,
miR 133 a可以靶向并降低低密度脂蛋白受体衔接蛋白1的表达,
(LDLRAP 1),一种衔接蛋白,其功能是内化LDL受体。突变的患者
LDLRAP 1具有LDL受体功能障碍,导致高脂血症和常染色体隐性遗传
高胆固醇血症(ARH)病症。目前还不清楚miR 133 a在调节细胞凋亡中的作用。
脂质摄取和动脉粥样硬化的发展。同样,也没有任何关于
LDLRAP 1表达、功能和参与VSMC泡沫细胞形成。我们报道说,
miR 133 a和LDLRAP 1均调节VSMC中oxLDL摄取。LDL RAP 1在VSMC中被oxLDL诱导,
在正常中膜VSMC中检测不到,但在损伤动脉的斑块和新生内膜VSMC中表达。
IL-19可降低VSMC中LDLRAP 1的表达和oxLDL的摄取。miR 133 a和LDLRAP 1均调节
VSMC增殖,以前未认识到这些分子的功能。初步研究表明
LDLRAP 1 +/-小鼠动脉粥样硬化增加,但再狭窄减少。在这个竞争激烈的
更新申请,我们假设LDLRAP 1可以在VSMC中选择性降低,因为miR 133 a
是肌肉特异性,VSMC摄取脂质的减少具有动脉粥样硬化保护作用,
血管增生综合征本应用程序的总体目标是确定
miR 133 a和LDLRAP 1在VSMC脂质摄取、增殖、动脉粥样硬化形成、胆固醇诱导表型中的作用
调制和血管再狭窄。
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)
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MICHAEL V AUTIERI其他文献
MICHAEL V AUTIERI的其他文献
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{{ truncateString('MICHAEL V AUTIERI', 18)}}的其他基金
Regulation of adipose tissue microvascular function by IL19
IL19对脂肪组织微血管功能的调节
- 批准号:
10686973 - 财政年份:2022
- 资助金额:
$ 53.57万 - 项目类别:
Regulation of adipose tissue microvascular function by IL19
IL19对脂肪组织微血管功能的调节
- 批准号:
10503662 - 财政年份:2022
- 资助金额:
$ 53.57万 - 项目类别:
Interleukin-19 Inhibits Atherosclerosis by Diverse Mechanisms
Interleukin-19 通过多种机制抑制动脉粥样硬化
- 批准号:
8594550 - 财政年份:2013
- 资助金额:
$ 53.57万 - 项目类别:
Interleukin-19 Inhibits Atherosclerosis by Diverse Mechanisms
Interleukin-19 通过多种机制抑制动脉粥样硬化
- 批准号:
8705581 - 财政年份:2013
- 资助金额:
$ 53.57万 - 项目类别:
Interleukin-19 Inhibits Atherosclerosis by Diverse Mechanisms
Interleukin-19 通过多种机制抑制动脉粥样硬化
- 批准号:
8878340 - 财政年份:2013
- 资助金额:
$ 53.57万 - 项目类别:
Mechanisms of Th2 interleukin-driven angiogenesis
Th2白细胞介素驱动的血管生成机制
- 批准号:
8666808 - 财政年份:2013
- 资助金额:
$ 53.57万 - 项目类别:
Mechanisms of Th2 interleukin-driven angiogenesis
Th2白细胞介素驱动的血管生成机制
- 批准号:
8508007 - 财政年份:2013
- 资助金额:
$ 53.57万 - 项目类别:
Mechanisms of Th2 interleukin-driven angiogenesis
Th2白细胞介素驱动的血管生成机制
- 批准号:
8837059 - 财政年份:2013
- 资助金额:
$ 53.57万 - 项目类别:
Suppression of VSMC Activation and Mechanisms of Vascular Protection by IL-19
IL-19抑制VSMC激活及血管保护机制
- 批准号:
8071157 - 财政年份:2009
- 资助金额:
$ 53.57万 - 项目类别:
Suppression of VSMC Activation and Mechanisms of Vascular Protection by IL-19
IL-19抑制VSMC激活及血管保护机制
- 批准号:
7654035 - 财政年份:2009
- 资助金额:
$ 53.57万 - 项目类别:
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