Circadian regulation of vascular aging

血管衰老的昼夜节律调节

• 批准号: 10094243
• 负责人: JOHN C CHATHAM
• 金额: $ 62.84万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-18 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094243
• 关键词: ARNTL gene; Age; Aging; Agonist; Alzheimer' s Disease; Animal Model; Animals; Arteries; Atherosclerosis; Blood Vessels; Cardiovascular Diseases; Cell Aging; Circadian Dysregulation; Circadian Rhythms; Clinical; Coronary Arteriosclerosis; Deposition; Diabetes Mellitus; Disease; Echocardiography; Extracellular Matrix; Extracellular Matrix Degradation; FOXO1A gene; Heart failure; Human; Hypertension; Impairment; Incidence; Intervention; Longevity; Malignant Neoplasms; Mass Spectrum Analysis; Medial; Metabolic Diseases; Metabolism; Molecular; Molecular Structure; Mus; Pathogenesis; Pathologic; Pathology; Pattern; Peripheral arterial disease; Phenotype; Physiological; Prevention strategy; Proteins; Proteomics; Public Health; Regulation; Signal Transduction; Smooth Muscle Myocytes; Stroke; Structure; Thick; Time; Vascular Diseases; Vascular Smooth Muscle; Vascular calcification; age related; arterial stiffness; calcification; cardiovascular disorder prevention; circadian; circadian pacemaker; circadian regulation; design; feeding; improved; in vivo; loss of function; migration; mineralization; normal aging; novel; osteogenic; prevent; senescence; transcription factor; translational impact; vascular smooth muscle cell proliferation

Vascular aging, the age-related molecular, structural and functional changes in the blood vessels, not only impairs normal vascular contraction and compliance but also increases the incidence of cardiovascular disease, including hypertension, coronary artery disease, heart failure, stroke and peripheral artery disease, as well as vascular complications in metabolic disease, such as diabetes. Therefore, better understanding of the molecular regulation of vascular aging may offer greater opportunities to identify promising targets for potential novel clinical interventions to prevent or retard vascular aging and age-related cardiovascular disease. The current application aims to fill the unmet scientific gaps to elucidate the molecular determinants in vascular aging. Vascular smooth muscle cell (VSMC) proliferation, migration, mineralization, extracellular matrix (ECM) deposition, and senescence contribute to age-related vascular structural and functional changes. As a result, increased medial and neointimal thickness, arterial stiffness, ECM degradation and calcification are manifestations of vascular aging, which promotes cardiovascular disease including atherosclerosis, hypertension, vascular calcification and stroke. We found that a key transcription factor Runx2 is elevated in an age-dependent manner, and SMC-specific deletion of Runx2 inhibited vascular complications that are more pronounced in aging, including atherosclerosis, neointimal formation and vascular calcification. Furthermore, Runx2 deficiency in VSMC inhibited the expression of VSMC matrix proteins and senescence, two hallmarks of VSMC aging, supporting a novel function of Runx2 in regulating vascular aging that is beyond its known function in regulating VSMC calcification. Mechanistically, we identified a previously unrecognized Runx2 oscillation in VSMC in culture as well as in mouse arteries in vivo. Runx2 oscillation in VSMC was associated with the oscillation of the key clock regulator, BMAL1, and the clock-regulated FOXO1. Coincidently, increased expression of BMAL1 and FOXO1 was demonstrated in aging arterials, similar to that of Runx2. With the use of loss-of-function approaches, our preliminary studies further demonstrated a causative function of circadian clock (BMAL1) and O-GlcNAcylation in regulating Runx2 expression. These results support the hypothesis that interplay of clock rhythm and protein O-GlcNAcylation promotes vascular aging through the FOXO/Runx2 signaling axis. Using novel inducible SMC-specific BMAL1, OGT and Runx2 deficient animal models, the proposal will characterize circadian clock-regulated vascular aging in mice (Aim 1); and delineate mechanisms underlying circadian regulation of vascular aging (Aim 2). Results from the proposed studies will develop a novel paradigm underlying vascular clock and O-GlcNAcylation regulation of the FOXO/Runx2 signaling axis in vascular aging, which will advance our understanding of basic mechanisms governing vascular aging. As vascular aging promotes many diseases, the novel mechanisms uncovered in this application should also have broad scientific and translational impact on increasing human lifespan and improving public health.

血管老化是指与年龄相关的血管分子、结构和功能的变化， 不仅损害正常的血管收缩和顺应性，而且还增加心血管疾病的发生率。 疾病，包括高血压、冠状动脉疾病、心力衰竭、中风和外周动脉疾病， 以及代谢疾病如糖尿病中的血管并发症。因此，更好地了解 血管老化的分子调节可能为确定潜在的有希望的靶点提供更多的机会。 预防或延缓血管老化和年龄相关性心血管疾病的新型临床干预措施。 目前的申请旨在填补未满足的科学空白，以阐明在基因组中的分子决定因素。 血管老化。血管平滑肌细胞（VSMC）增殖、迁移、矿化、细胞外基质 (ECM)沉积和衰老导致与年龄相关的血管结构和功能变化。作为 结果，中膜和新生内膜厚度增加，动脉僵硬，ECM降解和钙化， 血管老化的表现，促进心血管疾病，包括动脉粥样硬化， 高血压、血管钙化和中风。我们发现，一个关键的转录因子Runx 2在一个细胞中升高， 年龄依赖性方式，SMC特异性Runx 2缺失抑制血管并发症， 在衰老中显著，包括动脉粥样硬化、新生内膜形成和血管钙化。此外，委员会认为， VSMC中Runx 2缺陷抑制了VSMC基质蛋白的表达和衰老，这两个标志是VSMC的细胞周期。 VSMC老化，支持Runx 2在调节血管老化中的新功能，这超出了其已知的功能 调节VSMC钙化。从机制上讲，我们发现了一个以前未被识别的Runx 2振荡， 培养的VSMC以及体内小鼠动脉中的VSMC。VSMC的Runx 2振荡与VSMC的 关键时钟调节器BMAL 1和时钟调节FOXO 1的振荡。巧合的是， BMAL 1和FOXO 1的表达在老化动脉中得到证实，类似于Runx 2。与使用 功能丧失的方法，我们的初步研究进一步证明了生物钟的致病功能 （BMAL 1）和O-GlcNAc化在调节Runx 2表达中的作用。这些结果支持了以下假设： 生物钟节律和蛋白质O-GlcNAc化的相互作用通过 FOXO/Runx 2信号轴。使用新的可诱导SMC特异性BMAL 1、OGT和Runx 2缺陷动物 模型，该提案将描述小鼠昼夜节律时钟调节的血管老化（目标1）;并描述 血管衰老的昼夜节律调节机制（目的2）。拟议研究的结果将 开发一种新的模式，潜在的血管时钟和FOXO/Runx 2信号的O-GlcNAc化调节 轴在血管衰老中的作用，这将促进我们对血管衰老基本机制的理解。作为 血管老化促进了许多疾病，本申请中发现的新机制也应该具有 对延长人类寿命和改善公众健康产生广泛的科学和转化影响。