Sirt1, Vascular Aging, and Aortic Aneurysm

Sirt1、血管老化和主动脉瘤

• 批准号: 8719510
• 负责人: MING-HUI ZOU
• 金额: $ 30.34万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719510
• 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; Gelatinase A; Genetic; Health; Histone Deacetylase; Human; Incidence; Inflammation; Infusion procedures; Knock-out; Knockout Mice; Link; Longevity; Lower Organism; MMP2 gene; Mediating; Messenger RNA; Molecular; Molecular Genetics; Monitor; Mus; Nicotinamide adenine dinucleotide; Operative Surgical Procedures; Patients; Peptide Hydrolases; Population; Prevalence; 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; beta-Galactosidase; 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; promoter; response; senescence; therapeutic target

DESCRIPTION (provided by applicant): 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 β-galactosidase (SA-β-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 Ang II treatment. Mechanically, we found that increased levels of p21 in old aortas significantly enhance the binding of AP2α, a transcriptional factor activated by Ang II, 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 AP2α-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.

描述（由申请方提供）：腹主动脉瘤（AAA）是腹主动脉的永久性扩张，破裂后死亡率超过85%。目前，尚无经证实可减缓AAA进展和破裂的治疗策略，因此手术是唯一可用的选择。人类流行病学数据表明，老化是AAAs的主要危险因素。随着人口寿命的延长，预计AAA发病率将变得更加普遍。AAA患病率的上升，加上AAA破裂的高死亡率，明确支持了研究确定AAA形成和进展机制的必要性。尽管高龄是AAA的已知主要风险因素，但衰老加速AAA形成的分子基础仍然很大程度上未知。我们已经获得了令人兴奋的初步数据，表明年龄相关的抑制Sirt 1（NAD+依赖性脱乙酰酶）在血管平滑肌细胞（VSMC）的肾上腺髓质加重血管紧张素II触发的AAA。此外，血管紧张素（Ang）II，一个良好的表征AAA小鼠模型，输注显着降低Sirt 1活性。此外，在Sirt 1-VSMC特异性敲除（SV-KO）小鼠中，响应于Ang II的AAA的形成和破裂加速。同时，我们发现血管老化标志物[p21、p53和衰老相关β-半乳糖苷酶（SA-β-gal）阳性染色]在SV-KO小鼠的动脉中显著升高，但在SV-Tg小鼠的动脉中降低。最后，我们发现，Sirt 1消融增加了基质金属蛋白酶（MMP）2和MT 1-MMP的蛋白和mRNA水平后，Ang II治疗。从机制上讲，我们发现，老年人乳腺癌中p21水平的增加显著增强了AP 2 α（一种由Ang II激活的转录因子）与MMP 2启动子的结合，导致MMP 2的异常表达。因此，我们的中心假设是，老年动脉瘤中Sirt 1的氧化失活增加了p53/p21，这加剧了血管紧张素II诱导的VSMC和动脉瘤中AP 2 α介导的MMP 2表达。为了验证或反驳这一假设，我们提出了以下具体目标：（1）确定高龄或Ang II输注对Sirt 1活性的影响，并评估Sirt 1减少是否导致小鼠体内血管过早老化;（2）建立与年龄相关的Sirt 1减少加速Ang II诱导的血管壁破坏和动脉瘤形成;（3）阐明Sirt 1失活如何加速AAA。该申请具有很高的临床创新性和意义，因为我们预计该申请的完成将有助于将Sirt 1激活确定为预防高龄患者AAA发生、进展和破裂的新型潜在治疗靶点。