The Connection between Reactive Oxygen Species and Telomeres in Cardiovascular Di

活性氧与心血管疾病端粒之间的联系

• 批准号: 8205268
• 负责人: Carrie-Ann Jessica Olivia Gordon
• 金额: $ 3.1万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205268
• 关键词: Age; Americas; Antioxidants; Arterial Fatty Streak; Atherosclerosis; Biochemical; Biochemistry; Biological Assay; Biology; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cells; Cessation of life; Chromosomes; Clinical; Country; DNA Damage; Data; Development; Diagnosis; Diagnostic; Disease; Disease Marker; Disease Progression; Down-Regulation; Elements; Estrogens; Functional disorder; Goals; Guanine; Hypertension; Investigation; Length; Leukocytes; Measures; Modeling; Molecular; Morbidity - disease rate; Mus; Nature; Obesity; Oxidative Stress; Post-Transcriptional Regulation; Prevention; Production; Publishing; Reactive Oxygen Species; Regulation; Reporting; Research; Rest; Risk Factors; Role; Series; Smoking; Smooth Muscle Myocytes; Telomerase; Telomere Maintenance; Telomere Shortening; Testing; United States; Up-Regulation; Vitamin E; Wild Type Mouse; aged; base; human SOD2 protein; improved; in vivo; innovation; mortality; mouse model; research study; telomerase reverse transcriptase; telomere; therapeutic target

DESCRIPTION (provided by applicant): Atherosclerosis and the resulting cardiovascular disease (CVD) are the leading cause of mortality in the United States of America where one in every three deaths is attributed to CVD. Risk factors such as ageing, obesity, smoking and hypertension have been identified but the cause of the atherosclerosis is still unknown. Increased production of reactive oxygen species (ROS) and telomere dysfunction has been implicated in the development of atherosclerosis. ROS is considered a significant contributor to CVD and there is increased occurrence of shorten telomeres in atherosclerotic plaques. Additionally, shortened telomeres in leucocytes are associated with increased pre-disposition of CVD. Recently published reports have identified ROS as a regulator of TERT, the catalytic subunit of telomerase, which uses its enzymatic activity to maintain telomere length. The newly discovered relationship between ROS and TERT suggests that their roles in CVD are interconnected. However, the relationship between ROS and telomere maintenance in CVD progression is poorly understood, and it is not clear whether the relationship is causative or correlative. I hypothesize that the pro-atherosclerotic effects of ROS are in part the result of ROS action on telomere function. Here, I propose a series of studies to determine the effects of increased oxidative stress on telomere maintenance. For this proposal, I will utilize the aortic smooth muscle cells (SMCs) isolated from haplodeficient superoxide dismutase 2 (SOD2 ) mice, an established model used to study ROS contribution to atherosclerosis. This innovative use of SOD2 mouse allows me to directly assess telomere and telomerase status in an atherosclerotic model. For Aim 1, I will determine ROS effect on telomerase activity and the mechanisms of ROS regulation of telomerase. Preliminary data shows that telomerase activity is approximately 50% less in SOD2 SMCs compared to wild type (WT) SMCs confirming that increased oxidative stress decreases telomerase activity. In Aim 2, I will determine the effects of ROS on telomeres by measuring telomere lengths and telomere integrity. In Aim 3, I will determine if the anti-atherosclerotic agents estrogen and vitamin E reverse ROS-dependent deficits in telomere maintenance. The results from these studies will provide the basis for understanding ROS regulation of TERT in vivo (Aim 1), provide a direct assessment of the effects of ROS on telomeres (Aim 2) and determine if telomere maintenance is a target of anti-atherosclerotic agents (Aim3). Overall, the completion of the proposed research will elucidate a direct connection between ROS and telomere maintenance in CVD mechanism furthering our goal to form an accurate and complete understanding of the molecular basis of atherosclerosis. Increased understanding of CVD molecular mechanisms will improve strategies towards the treatment, prevention and diagnosis of CVD. PUBLIC HEALTH RELEVANCE: Reactive oxygen Species (ROS) and telomere dysfunction have been independently implemented in the atherosclerosis development but new evidence has emerged suggesting that their role in atherosclerosis is connected. Here I propose a series of experiments that examine the newly defined relationship between ROS and telomere dysfunction, in an effort to better understand the underlying causes of atherosclerosis.

描述（由申请人提供）：动脉粥样硬化和由此导致的心血管疾病（CVD）是美国死亡的主要原因，每三例死亡中就有一例归因于CVD。老年、肥胖、吸烟和高血压等危险因素已被确定，但动脉粥样硬化的原因仍不清楚。活性氧（ROS）的产生增加和端粒功能障碍与动脉粥样硬化的发展有关。ROS被认为是CVD的重要贡献者，并且在动脉粥样硬化斑块中缩短端粒的发生率增加。此外，白细胞中端粒缩短与CVD易感性增加相关。最近发表的报告已经确定ROS作为端粒酶催化亚基TERT的调节剂，其利用其酶活性来维持端粒长度。新发现的ROS和TERT之间的关系表明它们在CVD中的作用是相互关联的。然而，在CVD进展中ROS和端粒维持之间的关系知之甚少，并且不清楚这种关系是因果关系还是相关关系。我推测ROS的促动脉粥样硬化作用部分是由于ROS对端粒功能的作用。在这里，我提出了一系列研究来确定氧化应激增加对端粒维持的影响。对于这个建议，我将利用主动脉平滑肌细胞（SMC）分离自haplodeficient超氧化物歧化酶2（SOD 2）小鼠，一个既定的模型，用于研究ROS的动脉粥样硬化的贡献。SOD2小鼠的这种创新使用使我能够直接评估动脉粥样硬化模型中的端粒和端粒酶状态。目的1：研究ROS对端粒酶活性的影响，探讨ROS调控端粒酶活性的机制。初步数据显示，与野生型（WT）SMC相比，SOD2 SMC中的端粒酶活性低约50%，证实了增加的氧化应激降低了端粒酶活性。在目标2中，我将通过测量端粒长度和端粒完整性来确定ROS对端粒的影响。在目标3中，我将确定抗动脉粥样硬化药物雌激素和维生素E是否逆转端粒维持中ROS依赖性缺陷。这些研究的结果将为理解ROS对体内TERT的调节提供基础（Aim 1），提供ROS对端粒影响的直接评估（Aim 2），并确定端粒维持是否是抗动脉粥样硬化药物的靶点（Aim 3）。总体而言，完成拟议的研究将阐明ROS和端粒维持CVD机制之间的直接联系，进一步推动我们的目标，形成准确和完整的了解动脉粥样硬化的分子基础。增加对CVD分子机制的理解将改善CVD的治疗、预防和诊断策略。 公共卫生相关性：活性氧（ROS）和端粒功能障碍在动脉粥样硬化的发生发展中是独立的，但新的证据表明它们在动脉粥样硬化中的作用是相关的。在这里，我提出了一系列的实验，检查ROS和端粒功能障碍之间的新定义的关系，在努力更好地了解动脉粥样硬化的根本原因。