PTEN promoter hypermethylation underlies vascular disease progression
PTEN promoter hypermethylation underlies vascular disease progression
批准号:
10543851
负责人:
Mary Cm. Weiser-Evans
金额:
$57.37万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-01-20 至 2024-12-31
关键词:
AcuteAngiotensin IIArterial Fatty StreakArteriesAtherosclerosisAzacitidineBiological AssayBlood VesselsCRISPR/Cas technologyCellsChromatinChronicComplexCoronary arteryDNADNA MethylationDNA Modification MethylasesDataDisease ProgressionDown-RegulationEtiologyEventFibrosisGenesGenetic TranscriptionGenomicsHumanHypermethylationIn SituIn Situ HybridizationIn VitroInflammationInflammatoryInjuryKnockout MiceLigationMacrophageManuscriptsMediatingMethylationModelingMolecularMusMuscleMyelogenousNuclearPIK3CG genePTEN genePathogenicityPathologicPhenotypePhosphoric Monoester HydrolasesPlatelet-Derived Growth FactorPlayPublishingRegulationReporterRepressionRoleSignaling MoleculeSiteSmooth Muscle MyocytesStentsStimulusTestingTherapeuticTranscriptional RegulationUp-RegulationVascular DiseasesVascular Smooth MuscleVascular remodelingbisulfitecell dedifferentiationcofactordesignhigh throughput screeninghuman diseasein vivoinflammatory milieuinhibitormouse modelmyocardinneointima formationnovelnovel therapeuticspharmacologicpreservationpreventpromoterprotective effectpublic health relevancepyrosequencingrecruitrestenosissmall moleculetherapeutic targettranscription factor
中文摘要
摘要
动脉粥样硬化和再狭窄分别是慢性和急性炎症性血管疾病,
以显著的血管重塑为特征。驻留血管平滑肌细胞的表型转换
血管内皮细胞(SMC)在血管重塑中起着独特而关键的作用,是促进疾病进展的关键事件。而当
SMC表型调节的概念,标志是从分化的、收缩的表型转变为
去分化、促炎表型是公认的,调节这些SMC的机制
过渡是复杂的。重要的是,没有治疗方法可以防止SMC收缩功能的丧失
表型和炎症增加。我们先前证实,PTEN在调节细胞周期中起关键作用。
病理性血管重塑。PTEN失活促进去分化、炎症的SMC表型。
最近,我们将核PTEN的一个完全独特和必要的功能定义为转录辅助性蛋白。
调节SMC收缩基因的主转录因子SRF和SMC特异性miR-143/145
表达,及其肌肉特异性辅因子,肌钙蛋白。PTEN缺失阻止SRF-myocardin转录
活动。具有翻译意义的是,这种活性在正常和病变的人类冠状动脉中得到证实。
我们发现PTEN缺失与SMC去分化和动脉粥样硬化进展直接相关。
和复杂性。在这种情况下,调节PTEN丢失的机制尚不清楚。我们最近展示了
全身性PTEN升高钝化血管紧张素II(AngII)介导的血管重构和纤维化并阻断
动脉粥样硬化病变进展和损伤介导的新生内膜形成;这些影响与
保持收缩的SMC表型和减少的炎性微环境。因此,我们的数据
支持PTEN通过直接转录调控是分化的SMC表型的重要驱动因素
SMC收缩基因和一种致炎表型的抑制,并表明系统性PTEN
上调表达足以防止血管疾病的进展。最近推出的无偏高吞吐量屏幕
设计发现新的PTEN小分子激活剂揭示DNA甲基转移酶1
(DNMT1)抑制剂5-氮胞苷(5-aza)在转录水平上强烈上调PTEN,逆转
PDGF介导的SMC去分化和抑制DNA甲基胞嘧啶脱氧酶、TET2和
阻止病理性血管重塑。重要的是,这些效应在体外和体内都是通过
PTEN。我们认为PTEN基因的高甲基化是降低PTEN的一个重要机制
改善和促进病理性血管重塑(目标一)。此外,我们提出,血管
5-氮杂介导的保护作用是通过增加PTEN的表达、PTEN之间的串扰来实现的
和TET2,以及miR-143/145的下游调控(目标二)。最后,我们提出了增加PTEN
启动子超甲基化与动脉粥样硬化进展、DNMT1上调和
下调患病人体血管中TET2的表达(目标三)。
英文摘要
ABSTRACT
Atherosclerosis and restenosis are chronic and acute inflammatory vascular diseases, respectively,
characterized by significant vascular remodeling. Phenotypic switching of resident vascular smooth muscle cells
(SMCs) plays a unique and critical role in remodeling and is a key event promoting disease progression. While
the concept of SMC phenotypic modulation, marked by a shift from a differentiated, contractile phenotype to a
dedifferentiated, pro-inflammatory phenotype, is well-accepted, the mechanisms regulating these SMC
transitions are complex. Importantly, there are no therapeutics that prevent both the loss of the SMC contractile
phenotype and increased inflammation. We previously established that PTEN is critical in the regulation of
pathological vascular remodeling. PTEN inactivation promotes a dedifferentiated, inflammatory SMC phenotype.
More recently, we defined an entirely unique and essential function for nuclear PTEN as a transcriptional co-
factor with SRF, a master transcription factor regulating SMC contractile gene and SMC-specific miR-143/145
expression, and its muscle-specific cofactor, myocardin. PTEN loss prevents SRF-myocardin transcriptional
activity. Translationally significant, this activity was confirmed in normal and diseased human coronary arteries
as we established that PTEN loss directly correlated with SMC dedifferentiation and atherosclerosis progression
and complexity. The mechanism mediating loss of PTEN in this setting was unclear. We recently demonstrated
that systemic PTEN elevation blunts angiotensin II (AngII)-mediated vascular remodeling and fibrosis and blocks
atherosclerotic lesion progression and injury-mediated neointima formation; these effects are associated with
preservation of a contractile SMC phenotype and a reduced inflammatory microenvironment. Thus, our data
support that PTEN is an essential driver of the differentiated SMC phenotype through direct transcriptional control
of SMC contractile genes and repression of a proinflammatory phenotype and indicate that systemic PTEN
upregulation is sufficient to prevent vascular disease progression. A recent unbiased high throughput screen
designed to discover novel small molecule activators of PTEN revealed that the DNA methyltransferase 1
(DNMT1) inhibitor, 5-azacytidine (5-aza), robustly upregulates PTEN at the level of transcription, reverses
PDGF-mediated SMC dedifferentiation and repression of the DNA methylcytosine deoxygenase, TET2, and
blocks pathological vascular remodeling. Importantly, these effects both in vitro and in vivo are mediated via
PTEN. We propose that hypermethylation of the PTEN gene is an essential mechanism that reduces PTEN
levels and promotes pathological vascular remodeling (Aim One). In addition, we propose that the vascular
protective effects mediated by 5-aza are driven through increased PTEN expression, crosstalk between PTEN
and TET2, and downstream regulation of miR-143/145 (Aim Two). Finally, we propose that increased PTEN
promoter hypermethylation correlates with increased atherosclerosis progression, upregulation of DNMT1, and
downregulation of TET2 in diseased human vessels (Aim Three).
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PTEN promoter hypermethylation underlies vascular disease progression
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批准号:10330591
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项目类别:
-
资助金额:$57.37万
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财政年份:2021
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负责人:Mary Cm. Weiser-Evans
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依托单位:
PTEN-dependent regulation of SRF transcriptional activity and SMC phenotype control
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批准号:9247031
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项目类别:
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资助金额:$49.55万
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财政年份:2015
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负责人:Mary Cm. Weiser-Evans
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依托单位:
Reprogramming of mature smooth muscle cells to vascular progenitor cells
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批准号:8967222
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项目类别:
-
资助金额:$54.69万
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财政年份:2014
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负责人:Mary Cm. Weiser-Evans
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依托单位:
Microenvironmental Endogenous Reprogramming of Differentiated Smooth Muscle Cells
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批准号:8451768
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项目类别:
-
资助金额:$22.06万
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财政年份:2013
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负责人:Mary Cm. Weiser-Evans
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依托单位:
Microenvironmental Endogenous Reprogramming of Differentiated Smooth Muscle Cells
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批准号:8666806
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项目类别:
-
资助金额:$18.97万
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财政年份:2013
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负责人:Mary Cm. Weiser-Evans
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依托单位:
Role of PTEN in Vascular Lesion Formation
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批准号:8011968
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项目类别:
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资助金额:$37.19万
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财政年份:2009
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负责人:Mary Cm. Weiser-Evans
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依托单位:
Role of PTEN in Hypoxia-Induced Vascular Remodeling, Raphael Nemenoff
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批准号:7662790
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项目类别:
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资助金额:$32.14万
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财政年份:2009
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负责人:Mary Cm. Weiser-Evans
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依托单位:
Role of PTEN in Vascular Lesion Formation
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批准号:7580629
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项目类别:
-
资助金额:$37.37万
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财政年份:2009
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负责人:Mary Cm. Weiser-Evans
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依托单位:
Role of PTEN in Vascular Lesion Formation
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批准号:7754395
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项目类别:
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资助金额:$37.26万
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财政年份:2009
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负责人:Mary Cm. Weiser-Evans
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依托单位:
Role of PTEN in Vascular Lesion Formation
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批准号:8207875
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项目类别:
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资助金额:$36.82万
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财政年份:2009
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负责人:Mary Cm. Weiser-Evans
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依托单位:
PTEN and Perlecan in Reducing In-Stent Restenosis
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批准号:7230246
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项目类别:
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资助金额:$18.43万
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财政年份:2006
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负责人:Mary Cm. Weiser-Evans
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依托单位:
PTEN and Perlecan in Reducing In-Stent Restenosis
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批准号:7100371
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项目类别:
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资助金额:$22.67万
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财政年份:2006
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负责人:Mary Cm. Weiser-Evans
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依托单位:
EMBRYONIC GENES IN SMC GROWTH AFTER VASCULAR INJURY
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批准号:6527270
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项目类别:
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资助金额:$29.85万
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财政年份:2000
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负责人:Mary Cm. Weiser-Evans
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依托单位:
EMBRYONIC GENES IN SMC GROWTH AFTER VASCULAR INJURY
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批准号:6619442
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项目类别:
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资助金额:$29.84万
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财政年份:2000
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负责人:Mary Cm. Weiser-Evans
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依托单位:
EMBRYONIC GENES IN SMC GROWTH AFTER VASCULAR INJURY
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批准号:6402780
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项目类别:
-
资助金额:$29.86万
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财政年份:2000
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负责人:Mary Cm. Weiser-Evans
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依托单位:
EMBRYONIC GENES IN SMC GROWTH AFTER VASCULAR INJURY
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批准号:6192273
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项目类别:
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资助金额:$29.87万
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财政年份:2000
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负责人:Mary Cm. Weiser-Evans
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依托单位:
Role of PTEN in Hypoxia-Induced Vascular Remodeling, Raphael Nemenoff
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批准号:8502284
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项目类别:
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资助金额:$31.35万
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财政年份:--
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负责人:Mary Cm. Weiser-Evans
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依托单位:
Role of PTEN in Hypoxia-Induced Vascular Remodeling, Raphael Nemenoff
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批准号:8097486
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项目类别:
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资助金额:$32.04万
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财政年份:--
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负责人:Mary Cm. Weiser-Evans
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依托单位:
Role of PTEN in Hypoxia-Induced Vascular Remodeling, Raphael Nemenoff
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批准号:8293013
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项目类别:
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资助金额:$32.78万
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财政年份:--
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负责人:Mary Cm. Weiser-Evans
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依托单位:
Role of PTEN in Hypoxia-Induced Vascular Remodeling, Raphael Nemenoff
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批准号:8377980
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项目类别:
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资助金额:$36.19万
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财政年份:--
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负责人:Mary Cm. Weiser-Evans
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依托单位:
海外基金