Role of Plasminogen Activator Inhibitor-1 in Vascular Smooth Muscle Cell Stiffening and Senescence
纤溶酶原激活剂抑制剂 1 在血管平滑肌细胞硬化和衰老中的作用
基本信息
- 批准号:10512042
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-10-01 至 2025-09-30
- 项目状态:未结题
- 来源:
- 关键词:ActinsAdverse effectsAffectAgeAgingAlteplaseArteriesAtherosclerosisAtomic Force MicroscopyBiologyBloodBlood VesselsBlood coagulationBlood flowCardiacCardiovascular DiseasesCardiovascular PhysiologyCardiovascular systemCell AdhesionCell AgingCell divisionCell physiologyCellsClinicalClinical TrialsCytoskeletonDataDiseaseDrug TargetingF-ActinFibrosisFluorescence MicroscopyFocal AdhesionsGenerationsGeneticGlycolysisGoalsHeartHeart failureHospitalsHypertensionInflammationLDL-Receptor Related Protein 1LinkMeasurementMediatingMembrane PotentialsMissouriMitochondriaMusMyocardial InfarctionMyosin ATPaseOrganOxygen ConsumptionPathologicPathway interactionsPeripheral arterial diseasePharmaceutical PreparationsPhenotypePlasminogen Activator Inhibitor 1PlayProductionProtease InhibitorProtein SecretionProteinsProteolysisReactive Oxygen SpeciesRelaxationResearchRoleScientistSerpin SuperfamilySignal PathwaySmooth Muscle MyocytesStress FibersStretchingStrokeTestingTranslatingTreesUniversitiesUrokinaseVascular DiseasesVascular Smooth MuscleVeteransWorkarterial stiffnessblood pressure regulationblood pumpburden of illnesscandidate identificationcell motilityclinically relevantcofilinconditional knockoutconstrictiondaltonexperienceexperimental studyfatty acid oxidationfitnessin vivoinhibitorinnovationmedical schoolsmembermilitary veteranmitochondrial membranemouse modelmultidisciplinarynormal agingnovelnovel strategiespharmacologicpreventrecruitrespiratoryresponsesenescencetranscriptome sequencingvascular inflammation
项目摘要
Vascular smooth muscle cells (SMCs) are present throughout the arterial tree and play a central role in
cardiovascular physiology by regulating blood pressure and flow. Cardiovascular aging is characterized by
pathologic changes in SMCs that contribute in a major way to high-burden diseases affecting US veterans,
including hypertension, atherosclerosis, myocardial infarction, stroke, and peripheral artery disease. Two
important phenotypic changes that occur in SMCs with aging are 1) stiffening, which produces hypertension
and increases cardiac afterload, and 2) senescence, which is functionally defined as arrest of cell division and
assumption of the senescence-associated secretory phenotype (SASP), a driver of vascular inflammation and
fibrosis. Plasminogen activator inhibitor-1 (PAI-1), a member of the serpin superfamily of protease inhibitors, is
the primary inhibitor of tissue-type plasminogen activator (t-PA) and urokinase (u-PA) and an important
regulator of proteolysis and cell adhesion. PAI-1 expression increases with age and is associated with
vascular fibrosis and generalized cell senescence. However, the specific effects of PAI-1 on SMC stiffening
and senescence, as well as the mechanisms underlying them, are poorly understood. In preliminary studies
involving pharmacologic and genetic modulation of PAI-1 expression in SMCs, we have shown that drug
targeting of PAI-1 decreases SMC stiffness, assessed by atomic force microscopy (AFM), while also
decreasing SMC cytoskeleton formation and enhancing activation of cofilin, which degrades filamentous (F)-
actin. We also have demonstrated that PAI-1 promotes SMC senescence by a pathway involving the LDL
receptor-related protein-1 (LRP1), while also dampening mitochondrial respiratory fitness, which is strongly
linked to cell senescence. We have performed an RNA-sequencing analysis that has identified candidate
signaling pathways mediating PAI-1’s effects on SMC stiffness and senescence. We also have generated
mice with conditional knockout of PAI-1 in SMCs, which will enable us to study the significance of our findings
in vivo. Based on our extensive preliminary data, we hypothesize that PAI-1 1) regulates SMC stiffness by
controlling actin, myosin, and focal adhesion assembly in the cytoskeleton, and 2) promotes SMC senescence
through adverse effects on mitochondrial energy substrate utilization and reactive oxygen species accrual. To
test these hypotheses, we propose the following specific aims: 1) identify the intracellular signaling pathways
by which PAI-1 regulates SMC stress fiber formation and stiffness, 2) determine the role of PAI-1 in regulating
mitochondrial substrate utilization and reactive oxygen species accumulation in SMCs, probing underlying
mechanisms, and 3) study the effects of pharmacologic and SMC-specific inhibition of PAI-1 on arterial
stiffness and senescence in vivo. Several innovative strategies will be employed, including 1) AFM, 2)
confocal fluorescence microscopy, 3) quantitative studies of PAI-1’s effects of F-actin, myosin, and focal
adhesion assembly, 4) measurement of mitochondrial energy substrate utilization and membrane potential,
and 5) novel murine models that enable quantification of the effects of systemic inhibition and SMC-specific
deletion of PAI-1 on vascular stiffening and senescence in vivo. The experiments will be carried out by a
highly experienced, multi-disciplinary team of scientists from the Truman VA Hospital, the University of
Missouri School of Medicine, and the Dalton Cardiovascular Research Center. The significance of the
proposed work is that it will 1) identify mechanisms by which PAI-1 and its pharmacological inhibition regulate
key degenerative changes that occur in SMCs with aging, namely stiffening and senescence, and 2) translate
these findings to the in vivo setting. The proposed experiments will yield important new information about the
roles of PAI-1 and SMCs in vascular aging that are directly relevant to major cardiovascular diseases affecting
the US veteran population. The studies also have great potential for transition to the clinical setting through
the use of pharmacologic PAI-1 inhibitors.
血管平滑肌细胞(SMC)存在于整个动脉树中,并在动脉血管的形成和发展中发挥核心作用。
通过调节血压和流量来实现心血管生理学。心血管老化的特征是
SMC的病理变化是影响美国退伍军人的高负担疾病的主要原因,
包括高血压、动脉粥样硬化、心肌梗塞、中风和外周动脉疾病。两
随着年龄的增长,SMC中发生的重要表型变化是:1)硬化,其产生高血压
并增加心脏后负荷,和2)衰老,其在功能上被定义为细胞分裂的停滞,
衰老相关分泌表型(SASP)的假设,血管炎症的驱动因素,
纤维化纤溶酶原激活物抑制剂-1(派-1)是丝氨酸蛋白酶抑制剂超家族的成员,
组织型纤溶酶原激活物(t-PA)和尿激酶(u-PA)主要抑制剂,
调节蛋白水解和细胞粘附。派-1表达随年龄增长而增加,
血管纤维化和全身性细胞衰老。然而,派-1对SMC硬化的具体影响
和衰老,以及它们背后的机制,知之甚少。在初步研究中
涉及药物和基因调控派-1在SMC中的表达,我们已经证明药物
通过原子力显微镜(AFM)评估,靶向派-1降低SMC硬度,同时
减少SMC细胞骨架形成并增强cofilin的活化,其降解丝状(F)-
肌动蛋白。我们还证实派-1通过LDL介导的途径促进SMC衰老,
受体相关蛋白1(LRP 1),同时也抑制线粒体呼吸适应性,这是强烈的
与细胞衰老有关我们进行了RNA测序分析,
信号通路介导派-1对SMC刚度和衰老的影响。我们还产生了
条件性敲除SMCs中派-1的小鼠,这将使我们能够研究我们的发现的意义
in vivo.基于我们广泛的初步数据,我们假设派-1 1 1)通过以下途径调节SMC硬度:
控制细胞骨架中的肌动蛋白、肌球蛋白和粘着斑组装,以及2)促进SMC衰老
通过对线粒体能量底物利用和活性氧积累的不利影响。到
为了验证这些假设,我们提出了以下具体目标:1)确定细胞内信号通路
派-1调节SMC应力纤维形成和刚度的作用,2)确定派-1在调节SMC应力纤维形成和刚度中的作用,
线粒体底物的利用和活性氧的积累,探索潜在的
3)研究派-1的药理学和SMC特异性抑制对动脉粥样硬化的影响。
僵硬和衰老。将采用几种创新策略,包括1)AFM,2)
共聚焦荧光显微镜; 3)定量研究派-1对F-actin、myosin和focal
粘附组装,4)测量线粒体能量底物利用和膜电位,
和5)新的鼠模型,其能够定量全身抑制和SMC特异性抑制的作用,
派-1缺失对血管硬化和衰老的影响。实验将由一名
来自弗吉尼亚大学杜鲁门VA医院的经验丰富的多学科科学家团队
密苏里州医学院和道尔顿心血管研究中心。的意义
拟议的工作是:1)确定派-1及其药理学抑制调节的机制
SMC随着衰老发生的关键退行性变化,即硬化和衰老,以及2)翻译
将这些发现应用于体内环境。拟议的实验将产生关于
派-1和SMCs在血管老化中的作用与主要心血管疾病直接相关,
美国退伍军人。这些研究也有很大的潜力,通过过渡到临床环境,
药物派-1抑制剂的使用。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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William P Fay其他文献
William P Fay的其他文献
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{{ truncateString('William P Fay', 18)}}的其他基金
Role of Plasminogen Activator Inhibitor-1 in Vascular Smooth Muscle Cell Stiffening and Senescence
纤溶酶原激活剂抑制剂 1 在血管平滑肌细胞硬化和衰老中的作用
- 批准号:
10259921 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
- 批准号:
10312631 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
- 批准号:
10230468 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
- 批准号:
10475264 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
- 批准号:
10730211 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
- 批准号:
10022343 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
- 批准号:
10240635 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Midwest Biomedical Accelerator Consortium: MBArC
中西部生物医学加速器联盟:MBArC
- 批准号:
9897387 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Role of Plasminogen Activator Inhibitor-1 in Adipose Tissue Dysfunction and Atherosclerosis in Metabolic Syndrome
纤溶酶原激活剂抑制剂 1 在代谢综合征脂肪组织功能障碍和动脉粥样硬化中的作用
- 批准号:
9913573 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Role of Plasminogen Activator Inhibitor-1 in Adipose Tissue Dysfunction and Atherosclerosis in Metabolic Syndrome
纤溶酶原激活剂抑制剂 1 在代谢综合征脂肪组织功能障碍和动脉粥样硬化中的作用
- 批准号:
10155514 - 财政年份:2018
- 资助金额:
-- - 项目类别:
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