SIRT1, Vascular Aging and an Aortic Aneurysm
SIRT1,血管老化和主动脉瘤
基本信息
- 批准号:9059301
- 负责人:
- 金额:$ 29.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-08-15 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:Abdominal Aortic AneurysmAblationAgeAgingAneurysmAngiotensin IIAortaAortic AneurysmBindingBlood VesselsCell AgingCoupledDataDeacetylaseDevelopmentElderlyEquilibriumExtracellular Matrix DegradationGalactosidaseGelatinase AGeneticHistone DeacetylaseHumanIncidenceInflammationInfusion proceduresKnock-outKnockout MiceLinkLongevityMMP2 geneMediatingMessenger RNAMolecularMolecular GeneticsMonitorMusNicotinamide adenine dinucleotideOperative Surgical ProceduresPatientsPeptide HydrolasesPopulationPrevalencePrincipal InvestigatorProteinsRegulationResearchRisk FactorsRuptureRuptured Abdominal Aortic AneurysmSeveritiesSirtuinsSmokingSmooth Muscle MyocytesStaining methodStainsTestingTherapeuticTransgenic MiceUnited Statesabdominal aortaage relatedagedbasecell typeepidemiologic datagain of functionhuman MMP14 proteinin vivoinhibitor/antagonistinnovationloss of functionmacrophagemenmortalitymouse modelnoveloverexpressionprematurepreventprogramspromoterpublic health relevanceresponsesenescencetherapeutic target
项目摘要
Principal Investigator/Program Director (Last, first, middle): Zou, Minghui
Abdominal aortic aneurysms (AAAs) are permanent dilations of the abdominal aorta with over
85% mortality after rupture. Currently, there are no therapeutic strategies proven to blunt AAA
progression and rapture, making surgery as the only available option. Human epidemiologic
data indicates that aging is a major risk factor in AAAs. As the population lives longer, it is
anticipated that AAA incidence will become even more prevalent. The rising prevalence of
AAAs, coupled with the high mortality from ruptured AAA, clearly supports the need for research
to define mechanisms of AAA formation and progression. Despite that advanced age is a known
major risk factor for AAA, the molecular basis underlying aging-accelerated AAA formation
remains largely unknown. We have obtained exciting preliminary data showing that age-
associated inhibition of Sirt1 (an NAD+-dependent deacetylase) in vascular smooth muscle cells
(VSMCs) of suprarenal aortas accentuates Ang II-triggered AAAs.Further, infusion of angiotensin
(Ang) II, a well-characterized mouse model of AAA, significantly lowered Sirt1 activity. Moreover, the
formation and rupture of AAAs in response to Ang II were accelerated in Sirt1-VSMC-specific
knockout (SV-KO) mice. Concomitantly, we found vascular aging markers [p21, p53, and
Senescence Associated ȕ-galactosidase (SA-ȕ-gal)-positive staining)] were significantly elevated in
the aortas of SV-KO mice but were reduced in those from SV-Tg mice. Finally, we found that Sirt1
ablation increased the protein and mRNA level of matrix metalloproteinases (MMP) 2 and MT1-MMP
after AngII treatment. Mechanically, we found that increased levels of p21 in old aortas significantly
enhance the binding of AP2Į, a transcriptional factor activated by AngII, to the MMP2 promoter
resulting in aberrant expression of MMP2. Thus, our central hypothesis is that oxidative inactivation
of Sirt1 in aged aortas increases p53/p21, which exacerbates Ang II-induced AP2Į-mediated MMP2
expression in VSMCs and aneurysm. To validate or refute this hypothesis, we propose the
following specific aims: (1) determine the effects of advanced age or Ang II infusion on Sirt1
activity and evaluate if Sirt1 reduction causes premature vascular aging in mouse in vivo; (2)
establish that age-related Sirt1 reduction accelerates Ang II-instigated destruction of the vessel
wall and aneurysm formation in mice in vivo; and (3) elucidate how Sirt1 inactivation accelerates
AAA. This application has high clinically innovations and significance because we anticipate that
the completion of this application will help identify Sirt1 activation as a novel potential
therapeutic target for preventing AAA initiation, progression, and rapture in patients with
advanced ages.
Project Description Page 6
首席调查员/项目主任(最后、第一、中间):邹明辉
腹主动脉瘤(Aaa)是腹主动脉的永久性扩张。
破裂后死亡率为85%。目前,还没有被证明可以钝化aaa的治疗策略。
进展和狂喜,使手术成为唯一可用的选择。人类流行病学
数据表明,老龄化是AAA的主要风险因素。随着人口寿命的延长,它是
预计AAA的发病率将变得更加普遍。患病率不断上升的
AAAS,再加上破裂的AAA的高死亡率,显然支持了研究的必要性
目的:明确AAA的形成和发展机制。尽管年事已高是众所周知的
AAA的主要危险因素,这是衰老加速AAA形成的分子基础
在很大程度上仍不为人所知。我们已经获得了令人兴奋的初步数据,表明年龄-
血管平滑肌细胞Sirt1(一种依赖NAD+的脱乙酰酶)的联合抑制作用
肾上动脉(VSMCs)增强Ang II触发的AAA。此外,血管紧张素
(Ang)II,一个特征良好的AAA小鼠模型,显著降低Sirt1的活性。此外,
血管紧张素Ⅱ诱导的Sirt1-VSMC特异性AAA的形成和破裂
基因敲除(SV-KO)小鼠。与此同时,我们发现了血管衰老标记物[p21,p53,和
衰老相关ȕ-半乳糖苷酶(SA-ȕ-GAL)阳性染色)]显著高于
SV-KO组小鼠的主动脉明显缩小,而SV-TG组小鼠的主动脉明显缩小。最后,我们发现Sirt1
消融后基质金属蛋白酶2和MT1-MMP2的蛋白和mRNA水平升高
经过Angii治疗后。从机制上讲,我们发现老年主动脉中p21的水平显著升高。
增强血管紧张素Ⅱ激活的转录因子ap2Į与基质金属蛋白酶2启动子的结合
导致MMP2的异常表达。因此,我们的中心假设是氧化失活
Sirt1在老年动脉中的表达上调P53/p21,从而加重Ang II诱导的AP2Į介导的MMP2
在VSMCs和动脉瘤中的表达。为了验证或驳斥这一假设,我们提出了
以下具体目标:(1)确定高龄或Ang II输注对Sirt1的影响
体内Sirt1活性降低是否导致小鼠血管过早衰老;(2)
证实与年龄相关的Sirt1减少会加速Ang II对血管的破坏
3)阐明Sirt1失活是如何加速Sirt1失活的
AAA。这一应用具有很高的临床创新性和意义,因为我们预计
这项申请的完成将有助于确定Sirt1激活为一种新的潜在
预防腹主动脉瘤患者发生、进展和狂喜的治疗目标
年事已高。
项目说明第6页
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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{{ truncateString('MING-HUI ZOU', 18)}}的其他基金
Prevention of high fat diet-induced vascular injury
预防高脂饮食引起的血管损伤
- 批准号:
8610941 - 财政年份:2010
- 资助金额:
$ 29.84万 - 项目类别:
Prevention of high fat diet-induced vascular injury
预防高脂饮食引起的血管损伤
- 批准号:
8440776 - 财政年份:2010
- 资助金额:
$ 29.84万 - 项目类别:
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