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

首席研究员/计划主管（最后，第一，中间）：Zou，Minghui 腹主动脉瘤（AAAS）是腹主动脉的永久扩张 破裂后85％死亡率。目前，没有证明AAA的治疗策略 进展和狂喜，使手术成为唯一可用的选择。人流行病学 数据表明衰老是AAA的主要危险因素。随着人口的寿命更长，它是 预计AAA事件将变得更加普遍。普遍存在的 AAA，加上AAA破裂的高死亡率，显然支持研究的需求 定义AAA形成和进展的机制。尽管如此，高龄还是已知的 AAA的主要危险因素，分子基础衰老的基础AAA形成 仍然是未知的。我们获得了令人兴奋的初步数据，表明年龄 血管平滑肌细胞中SIRT1（NAD+依赖性脱乙酰基酶）的相关抑制作用 （vsmcs）上主动脉的（vsmcs）加入ANG II触发的AAAS。 （ANG）II，AAA的特征良好的小鼠模型，显着降低了SIRT1活性。而且， SIRT1-VSMC特异 敲除（SV-KO）小鼠。同时，我们发现了血管衰老标记[P21，P53和 衰老相关的ȕ-半乳糖苷酶（SA-ȕ-GAL）阳性染色）]显着升高 SV-KO小鼠的主动脉，但在SV-TG小鼠中减少了。最后，我们发现SIRT1 消融增加了基质金属蛋白酶（MMP）2和MT1-MMP的蛋白质和mRNA水平 Angii治疗后。机械上，我们发现旧主动脉中P21的水平升高显着 增强ANGII激活的转录因子AP2į与MMP2启动子的结合 导致MMP2异常表达。这是我们的中心假设是氧化失活 老年主动脉中的SIRT1增加了p53/p21，这加剧了ANG II诱导的AP2į介导的MMP2 在VSMC和动脉瘤中的表达。为了验证或反驳这一假设，我们提出了 以下特定目的：（1）确定高级年龄或ANG II输注对SIRT1的影响 活性并评估SIRT1的减少是否导致体内小鼠小鼠的过早血管老化； （2） 确定与年龄相关的SIRT1还原可加速船只的ANG II污染破坏 体内小鼠的壁和动脉瘤形成； （3）阐明SIRT1灭活方式如何加速 AAA。该应用程序具有很高的临床创新和意义，因为我们预计 该应用程序的完成将有助于识别SIRT1激活是一种新型潜力 预防AAA倡议，进展和狂喜的治疗靶点 高级年龄。 项目说明第6页