Thrombogenic susceptibility in middle aged Veterans

中年退伍军人的血栓形成易感性

• 批准号: 10196967
• 负责人: Sanjana Dayal
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196967
• 关键词: Adult; Adverse effects; Age; Age of Onset; Aging; Agonist; Bioenergetics; Blood Platelets; Blood Vessels; Blood coagulation; Caring; Chronic; Data; Deacetylase; Development; Diabetes Mellitus; Elderly; Electron Transport; Event; Exhibits; Future; Health Care Costs; Hospitalization; Human; Hyperactivity; Incidence; Lead; Life; Mediating; Metabolic; Mitochondria; Mitochondrial Proteins; Morbidity - disease rate; Mus; Myocardial Infarction; Obesity; Outcome; Patients; Phenotype; Pilot Projects; Platelet Activation; Prediabetes syndrome; Predisposition; Prevention strategy; Proteins; Quality of life; Reaction; Reactive Oxygen Species; Regulation; Risk; Risk Factors; Role; SOD2 gene; Sirtuins; Source; Stroke; Superoxides; System; Testing; Thrombosis; Thrombus; Tissues; Veterans; Veterans Health Administration; age effect; age related; aged; aging gene; anti aging; antioxidant enzyme; base; burden of illness; cardiovascular risk factor; circulating biomarkers; cohort; early onset; high risk; metabolomics; middle age; mortality; novel; platelet function; stroke event; thrombogenesis; thrombotic; thrombotic complications

A primary cause of morbidity and mortality in the elderly is thrombotic complications, including myocardial infarction and stroke, and these events are the leading cause of hospitalization in Veteran Health Administration (VA) system. However, the mechanisms of thrombosis due to aging are understudied in VA patients. Secondly, risk factors that are encountered during mid- life may exacerbate outcome or lead to an early event in life. For example, due to obesity endemic the incidence of pre-diabetes in US is increasing, with current estimates indicating that 37% of adults are pre-diabetic. Amongst Veterans one in four have diabetes, and over 70% of Veterans receiving VA care are obese. Likewise, a high incidence of prediabetes is also apparent in VA patients. Given Veterans are at higher risk for cardiovascular events which are frequently associated with previously undiagnosed diabetes, understanding early age-related mechanisms in mid-life Veterans with or without prediabetes is necessary to develop preventive strategies for future vascular events. We have established that increased thrombotic susceptibility in middle-aged/older mice is associated with increased platelet activation and reactive oxygen species (ROS) accumulation, though the underlying mechanisms are unclear. In pilot studies, we have made the novel observation that sirtuin 3 (SIRT3), a well-established anti-aging gene, is markedly decreased in platelets from aged vs. young human or mice. SIRT3 is a mitochondrial deacetylase that finely controls the activity of several electron transport chain (ETC) proteins and superoxide dismutase 2 (SOD2) to cumulatively regulate ROS levels, but its role in platelet activation is not clear. We have now generated proof of principle data demonstrating that inhibition of SIRT3 leads to increased platelet activation and its activation reduces aggregation. Therefore, our central hypothesis is that, in middle aged Veterans, loss of SIRT3 promotes mitochondrial ROS accumulation in platelets, leading to platelet hyperactivity and increased thrombotic susceptibility, and that this phenotype is accentuated by presence of obesity and pre-diabetes. Specific Aim 1 will define the mechanistic role of SIRT3 in regulation of mitochondrial ROS levels, platelet activation and increased thrombotic susceptibility in mid- life Veterans. Specific Aim 2 will examine whether pre-diabetes modulates early-age onset of SIRT3-mediated mitochondrial ROS accumulation, platelet hyperactivation and exacerbates thrombotic susceptibility in mid-life Veterans.

老年人发病和死亡的主要原因是血栓并发症，包括 心肌梗死和中风，这些事件是住院的主要原因 退伍军人健康管理局 (VA) 系统。然而，血栓形成的机制 VA 患者的衰老情况尚未得到充分研究。其次，中期遇到的风险因素。 生活可能会加剧结果或导致生命中的早期事件。例如，由于肥胖 在美国，糖尿病前期的发病率正在上升，目前的估计表明 37% 的成年人处于糖尿病前期。退伍军人中有四分之一患有糖尿病，超过 70% 的退伍军人患有糖尿病 接受退伍军人管理局护理的退伍军人都很肥胖。同样，糖尿病前期的发病率也很高 VA 患者中明显。鉴于退伍军人发生心血管事件的风险较高， 经常与以前未诊断的糖尿病相关，了解早期年龄相关的 患有或不患有糖尿病前期的中年退伍军人的机制对于制定预防措施是必要的 未来血管事件的策略。我们已经确定血栓形成增加 中年/老年小鼠的易感性与血小板活化增加和 活性氧（ROS）积累，但其潜在机制尚不清楚。 在试点研究中，我们发现了一个新的观察结果：sirtuin 3 (SIRT3)，一种成熟的 与年轻人或小鼠相比，老年人的血小板中的抗衰老基因显着减少。 SIRT3 是一种线粒体脱乙酰酶，可精细控制多个电子传递链的活性 (ETC) 蛋白和超氧化物歧化酶 2 (SOD2) 累积调节 ROS 水平，但其 在血小板活化中的作用尚不清楚。我们现在已经生成了原理数据证明 证明抑制 SIRT3 会导致血小板活化增加及其活化 减少聚集。因此，我们的中心假设是，在中年退伍军人中，损失 SIRT3 促进血小板中线粒体 ROS 积累，导致血小板过度活跃 和血栓易感性增加，并且这种表型因存在 肥胖和糖尿病前期。具体目标 1 将定义 SIRT3 在监管中的机制作用 中期线粒体 ROS 水平、血小板活化和血栓易感性增加 生活退伍军人。具体目标 2 将检查糖尿病前期是否会调节糖尿病的早期发病 SIRT3 介导的线粒体 ROS 积累、血小板过度活化并加剧 中年退伍军人的血栓易感性。