Neutrophils play a pivotal role in vascular aging
Neutrophils play a pivotal role in vascular aging
批准号:
10637703
负责人:
Zhen Yue Jiang
金额:
$58.34万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-03-22 至 2027-02-28
关键词:
AcetylationAgingAmilorideAnimalsAortaB-LymphocytesBMP2 geneBlood PressureBlood VesselsC57BL/6 MouseCXC ChemokinesCardiovascular DiseasesCell Adhesion MoleculesCellsChronicCytoplasmic GranulesDNA BindingDataDeacetylaseDevelopmentDietDiseaseElastasesEndotheliumEventExtracellular MatrixExtravasationFatty acid glycerol estersFemaleFibrosisFructoseHumanImmuneIn VitroInfiltrationInflammationInflammatoryInjuryKnock-outKnockout MiceLeucocytic infiltrateLeukocyte ElastaseLeukocytesLongevityMADH2 geneMeasuresMedialMediatingMediatorMolecularMusNeutrophil InfiltrationNuclear TranslocationObesityOralOxidantsPAR-2 ReceptorPathologicPathway interactionsPeptide HydrolasesPermeabilityPhenotypePhosphotransferasesPhysiologic pulsePlayPrevalenceProcessProductionRegulationReportingResistanceRoleSIRT1 geneSerine ProteaseSignal PathwaySignal TransductionSiteSmooth MuscleSmooth Muscle MyocytesTestingTherapeutic EffectTissuesTransforming Growth Factor betaVascular DementiaVascular Endothelial CellVascular EndotheliumVascular PermeabilitiesVascular Smooth MuscleVascular remodelingage relatedagedarterial stiffnesscalcificationchemokine receptorconnective tissue growth factorepithelial Na+ channelfeedingin vivomalemigrationmouse modelneutrophilneutrophil elastase inhibitornovelnovel therapeutic interventionobesogenicosteogenicprogenitorprotective effecttissue injuryvascular endothelium permeabilityvascular injury
中文摘要
摘要
动脉僵硬是血管老化的标志,与心血管疾病事件增加和
血管性痴呆。炎症损伤和细胞外基质重塑被认为是主要的
血管损伤和动脉僵硬的病理原因。然而,启动的分子机制
并在大血管中传播与衰老相关的病理变化尚不清楚。在此,我们建议
研究中性粒细胞弹性蛋白酶(NE)在引发血管渗漏中的作用。
肥胖和非肥胖老年小鼠的炎症和纤维化。中性粒细胞是最丰富的
白血球,寿命短,在引发组织损伤和炎症中起着关键作用。我们的数据
结果表明:(1)脉搏波速度(PWV)是反映动脉僵直的主要参数。
NE基因敲除(NEKO)小鼠与其野生型窝种的比较,以及(2)NEKO小鼠对其具有抵抗力
与衰老相关的炎症、纤维化和主动脉钙化。我们还观察到去甲肾上腺素有很强的作用
关于增加血管内皮细胞通透性和增强主动脉平滑肌细胞纤维化的研究
成骨表型开关。此外,NE通过降解中性粒细胞致炎表型来调节中性粒细胞的致炎表型
长寿调节剂Sirtuin 1(Sirt1)。根据我们的初步数据,我们假设促炎因子
中性粒细胞与血管相互作用,通过释放去甲肾上腺素引起血管损伤和重塑。
后者导致血管通透性增加、纤维重塑和血液中的钙化。
船只。因此,抑制NE可能对衰老相关的血管损伤、纤维化重塑、
钙化,以及随后的动脉僵硬。这个RO1提案的目标是探索中性粒细胞如何
和去甲肾上腺素调节衰老过程中动脉壁的炎性重塑
肥胖的饮食。我们将探讨去甲肾上腺素是否通过激活蛋白水解酶来促进血管衰老
受体2(PAR2)和上皮钠通道(ENaC)信号通路在血管内皮细胞和
血管平滑肌细胞的体外和体内研究。此外,我们还将研究NE-Sirt1的作用
中性粒细胞表型调控与增龄相关血管损伤和重塑的信号通路
老鼠。最后,我们将评估选择性去甲肾上腺素抑制剂对衰老相关动脉的潜在治疗效果。
小鼠的僵硬。该项目的成功完成将为血管老化提供一种新的治疗策略
以及相关的疾病。
英文摘要
Abstract
Arterial stiffness is a hallmark of vascular aging and is related to increased cardiovascular disease events and
vascular dementias. Inflammatory damage and extracellular matrix remodeling have been proposed as the major
pathological causes of vascular injury and arterial stiffness. However, the molecular mechanisms that initiate
and propagate aging-related pathological changes in large blood vessels remain unclear. Here, we propose to
study the role of neutrophil elastase (NE), a neutrophil-specific protease, in initiating vascular leakage,
inflammation and fibrosis in aged mice both with and without obesity. Neutrophils are the most abundant
leukocytes, have a short lifespan, and play a critical role in initiating tissue damage and inflammation. Our data
demonstrated (1) that pulse wave velocity (PWV), the primary parameter of arterial stiffness, was decreased in
NE knockout (NEKO) mice compared to their wild-type littermates, and (2) that NEKO mice were resistant to
aging-related inflammation, fibrosis and calcification in the aorta. We also observed that NE has potent effects
on increasing vascular endothelial permeability and enhancing aortic smooth muscle cell fibrogenic and
osteogenic phenotypic switch. Further, NE regulates neutrophil proinflammatory phenotype by degrading
longevity regulator Sirtuin 1 (Sirt1). Based on our preliminary data, we hypothesize that pro-inflammatory
neutrophils interact with blood vessels, causing vascular damage and remodeling through the release of NE.
The latter contributes to the increased vascular permeability, fibrotic remodeling and calcification in the blood
vessels. Thus, inhibiting NE may lead to protective effects on aging-related vascular damage, fibrotic remodeling,
calcification, and subsequent arterial stiffness. The objective of this RO1 proposal is to explore how neutrophils
and NE regulate inflammatory remodeling in the arterial wall during the aging process with or without feeding of
an obesogenic diet. We will explore whether NE contributes to vascular aging by activating protease-activated
receptor 2 (PAR2) and epithelium sodium channel (ENaC) signaling pathways in vascular endothelial cells and
vascular smooth muscle cells with both in vitro and in vivo studies. Also, we will examine the role of the NE–Sirt1
signaling pathway in the regulation of neutrophil phenotype and aging-related vascular injury and remodeling in
mice. Finally, we will evaluate potential therapeutic effects of a selective NE inhibitor on aging-related arterial
stiffness in mice. Successful completion of this project will provide a novel therapeutic strategy for vascular aging
and related diseases.
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科研奖励(0)
会议论文
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批准号:10477430
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项目类别:
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资助金额:$41.52万
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海外基金