Smad2 in vascular smooth muscle homeostasis
Smad2 在血管平滑肌稳态中的作用
基本信息
- 批准号:10062643
- 负责人:
- 金额:$ 50.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-12 至 2022-11-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAgeAgingAmericanAngiotensin IIArteriesAttenuatedBaroreflexBasic ScienceBlood PressureBlood VesselsCardiovascular DiseasesCell AgingCellsCentral ArteryCollagenCore FacilityCoronary ArteriosclerosisDataDefectDevelopmentElasticityElastinEnvironmentEquipmentExtracellular MatrixGeneticGenetic TranscriptionGoalsHeart DiseasesHeart failureHistologicHomeostasisHumanHypertensionImpairmentIn VitroKidneyKnockout MiceKnowledgeLaboratoriesLeadLinkLiverLungMechanicsMedialMediatingMolecularMusNeural Crest CellOrganOutcomePharmacologyPhenotypePlayPositioning AttributePremature aging syndromePrevention strategyPrevention therapyProcessProductionPulse PressureResearchResistance developmentResistant HypertensionResourcesRiskRisk FactorsRoleSmooth Muscle MyocytesStrokeStructural defectStructureTP53 geneTechniquesTestingTherapeuticTissuesTreatment EfficacyUniversitiesVascular Smooth Muscleagedanimal facilityarterial stiffnessattenuationblood pressure regulationcardiovascular risk factorclinical applicationgain of functiongenetic approachin vivoinventionloss of functionmechanical propertiesmouse modelnovelnovel strategiesnovel therapeuticsprematurepressureprograms
项目摘要
Summary/Abstract
Aberration of vascular smooth muscle cell (SMC) phenotypes cause structural defects and impaired mechanical
properties of artery wall, leading to artery stiffness, which correlates with high blood pressure and is an
independent risk factor for the resistant hypertension. It is well-known that arterial wall stiffens with aging. In
addition to hypertension, vascular aging is an independent risk factor for cardiovascular diseases including
coronary artery disease, stroke and heart failure. However, the factors and mechanisms that control vascular
aging, especially SMC aging and artery stiffness, remain largely unknown. Our exciting preliminary data
demonstrate that Smad2 plays a critical role in maintaining SMC and vascular homeostasis and blood pressure.
SMC-tissue specific deficiency of Smad2 (Smad2sm-/-) in mice causes alterations in elastin and collagen content
and structure in the vessel wall, resulting in decreased artery distensibility, increased pulse pressure (indicator
of artery stiffness), and increased mean artery pressure. The vascular wall remodeling/stiffness in Smad2 SMC-
deficient mice appears to be caused by a premature SMC aging with an elevation in p53 level. In fact, the
increase in p53 level along with the decrease in Smad2 expression in artery SMC correlates with the aging in
mouse and human. Importantly, the correlation of decreased Smad2 with increased p53 is also closely
associated with the onset of hypertension in human. These data strongly support a novel hypothesis that
Smad2 maintains vascular homeostasis and blood pressure by inhibiting p53 expression and/or activity in SMC.
Using primary culture of SMCs, in vivo Smad2 and p53 SMC-specific knockout mouse models combining with
molecular, cellular, histological, and pharmacological approaches, we will 1) test if Smad2 is essential for
maintaining the vascular wall elasticity and blood pressure homeostasis; 2) elucidate the mechanism by which
Smad2 regulates SMC homeostasis through inhibiting p53 expression/activity; and 3) determine if blockade of
p53 attenuates Smad2 deficiency-caused artery stiffness and hypertension. Successful completion of the
proposed study will establish a novel mechanism regulating SMC aging and blood pressure homeostasis. It will
also allow us to identify potential novel approaches that may be used to develop effective therapeutics for treating
aging or artery stiffness-related hypertension.
摘要/摘要
血管平滑肌细胞(SMC)表型的像差导致结构缺陷和机械性障碍
动脉壁的特性,导致动脉僵硬,这与高血压相关,是
抗性高血压的独立危险因素。众所周知,动脉壁随老化而变硬。在
除了高血压外,血管衰老是心血管疾病的独立危险因素
冠状动脉疾病,中风和心力衰竭。但是,控制血管的因素和机制
衰老,尤其是SMC衰老和动脉僵硬,在很大程度上尚不清楚。我们令人兴奋的初步数据
证明SMAD2在维持SMC和血管稳态和血压方面起着至关重要的作用。
小鼠中Smc-Tissue特异性缺陷(SMAD2SM - / - )引起弹性蛋白和胶原蛋白含量的改变
和血管壁的结构,导致动脉降低,脉压增加(指示器)
动脉刚度)和平均动脉压力增加。 SMAD2 SMC-中的血管壁重塑/刚度
不足的小鼠似乎是由p53水平升高的过早SMC老化引起的。实际上,
p53水平的增加以及动脉SMC中SMAD2表达的降低与衰老相关
老鼠和人类。重要的是,SMAD2降低与p53增加的相关性也很紧密
与人类高血压发作有关。这些数据强烈支持一个新的假设
SMAD2通过在SMC中抑制p53表达和/或活性来维持血管稳态和血压。
使用SMC的一级培养,体内SMAD2和P53 SMC特异性敲除鼠标模型与
分子,细胞,组织学和药理学方法,我们将测试SMAD2是否必不可少
保持血管壁弹性和血压稳态; 2)阐明该机制
SMAD2通过抑制p53表达/活性来调节SMC稳态; 3)确定是否封锁
p53减弱了SMAD2缺乏引起的动脉僵硬和高血压。成功完成
拟议的研究将建立一种调节SMC衰老和血压稳态的新型机制。会
还允许我们识别可能用于开发有效治疗的有效治疗剂的潜在新方法
衰老或动脉刚度相关的高血压。
项目成果
期刊论文数量(27)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Nanoparticle endothelial delivery of PGC-1α attenuates hypoxia-induced pulmonary hypertension by attenuating EndoMT-caused vascular wall remodeling.
- DOI:10.1016/j.redox.2022.102524
- 发表时间:2022-12
- 期刊:
- 影响因子:11.4
- 作者:Cai, Dunpeng;Chen, Shi-You
- 通讯作者:Chen, Shi-You
A Novel Mechanism Underlying Inflammatory Smooth Muscle Phenotype in Abdominal Aortic Aneurysm.
- DOI:10.1161/circresaha.121.319374
- 发表时间:2021-10-29
- 期刊:
- 影响因子:20.1
- 作者:Cai D;Sun C;Zhang G;Que X;Fujise K;Weintraub NL;Chen SY
- 通讯作者:Chen SY
ADAR1 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice.
ADAR1 缺陷可防止小鼠高脂饮食引起的肥胖和胰岛素抵抗。
- DOI:10.1152/ajpendo.00175.2020
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Cui,Xiao-Bing;Fei,Jia;Chen,Sisi;Edwards,GaylenL;Chen,Shi-You
- 通讯作者:Chen,Shi-You
Response by Cui et al to Letter Regarding Article, "RGC-32 (Response Gene to Complement 32) Deficiency Protects Endothelial Cells From Inflammation and Attenuates Atherosclerosis".
Cui 等人对有关文章“RGC-32(补体 32 的响应基因)缺乏可保护内皮细胞免受炎症并减轻动脉粥样硬化”的信件的回应。
- DOI:10.1161/atvbaha.118.311146
- 发表时间:2018
- 期刊:
- 影响因子:0
- 作者:Cui,Xiao-Bing;Luan,Jun-Na;Dong,Kun;Chen,Sisi;Wang,Yongyi;Watford,WendyT;Chen,Shi-You
- 通讯作者:Chen,Shi-You
Smooth Muscle Cells Move With Mitochondria.
平滑肌细胞与线粒体一起移动。
- DOI:10.1161/atvbaha.118.311085
- 发表时间:2018
- 期刊:
- 影响因子:0
- 作者:Shi,Ning;Chen,Shi-You
- 通讯作者:Chen,Shi-You
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Shiyou Chen其他文献
Shiyou Chen的其他文献
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{{ truncateString('Shiyou Chen', 18)}}的其他基金
Novel Mechanisms Underlying the Development of Atherosclerosis
动脉粥样硬化发展的新机制
- 批准号:
10589484 - 财政年份:2023
- 资助金额:
$ 50.53万 - 项目类别:
Dedicator of cytokinesis 2 in abdominal aortic aneurysm
腹主动脉瘤胞质分裂2的奉献者
- 批准号:
10417112 - 财政年份:2019
- 资助金额:
$ 50.53万 - 项目类别:
Dedicator of cytokinesis 2 in abdominal aortic aneurysm
腹主动脉瘤胞质分裂2的奉献者
- 批准号:
10063651 - 财政年份:2019
- 资助金额:
$ 50.53万 - 项目类别:
Dedicator of cytokinesis 2 in abdominal aortic aneurysm
腹主动脉瘤胞质分裂2的奉献者
- 批准号:
10199018 - 财政年份:2019
- 资助金额:
$ 50.53万 - 项目类别:
Novel mechanism of smooth muscle phenotypic modulation and vascular remodeling
平滑肌表型调节和血管重塑的新机制
- 批准号:
8794466 - 财政年份:2014
- 资助金额:
$ 50.53万 - 项目类别:
Novel mechanism of smooth muscle phenotypic modulation and vascular remodeling
平滑肌表型调节和血管重塑的新机制
- 批准号:
8653749 - 财政年份:2014
- 资助金额:
$ 50.53万 - 项目类别:
Dedicator of Cytokinesis 2 in smooth muscle phenotype modulation
细胞分裂 2 在平滑肌表型调节中的奉献者
- 批准号:
8998055 - 财政年份:2014
- 资助金额:
$ 50.53万 - 项目类别:
Dedicator of Cytokinesis 2 in smooth muscle phenotype modulation
细胞分裂 2 在平滑肌表型调节中的奉献者
- 批准号:
8724068 - 财政年份:2014
- 资助金额:
$ 50.53万 - 项目类别:
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