SIRT1, Vascular Aging and an Aortic Aneurysm

SIRT1，血管老化和主动脉瘤

• 批准号: 9059301
• 负责人: MING-HUI ZOU
• 金额: $ 29.84万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9059301
• 关键词: Abdominal Aortic Aneurysm; Ablation; Age; Aging; Aneurysm; Angiotensin II; Aorta; Aortic Aneurysm; Binding; Blood Vessels; Cell Aging; Coupled; Data; Deacetylase; Development; Elderly; Equilibrium; Extracellular Matrix Degradation; Galactosidase; Gelatinase A; Genetic; Histone Deacetylase; Human; Incidence; Inflammation; Infusion procedures; Knock-out; Knockout Mice; Link; Longevity; MMP2 gene; Mediating; Messenger RNA; Molecular; Molecular Genetics; Monitor; Mus; Nicotinamide adenine dinucleotide; Operative Surgical Procedures; Patients; Peptide Hydrolases; Population; Prevalence; Principal Investigator; Proteins; Regulation; Research; Risk Factors; Rupture; Ruptured Abdominal Aortic Aneurysm; Severities; Sirtuins; Smoking; Smooth Muscle Myocytes; Staining method; Stains; Testing; Therapeutic; Transgenic Mice; United States; abdominal aorta; age related; aged; base; cell type; epidemiologic data; gain of function; human MMP14 protein; in vivo; inhibitor/antagonist; innovation; loss of function; macrophage; men; mortality; mouse model; novel; overexpression; premature; prevent; programs; promoter; public health relevance; response; senescence; therapeutic target

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