Circadian regulation of vascular aging

血管衰老的昼夜节律调节

• 批准号: 10323289
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323289
• 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; Mus; Pathogenesis; Pathologic; Pathology; Pattern; Peripheral arterial disease; Phenotype; Physiological; Prevention strategy; Proteins; Proteomics; Public Health; Regulation; Signal Transduction; Smooth Muscle Myocytes; Stroke; 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，与年龄相关的分子，结构和功能变化，而不是 仅会损害正常的血管收缩和依从性，但也会增加心血管的发生率 疾病，包括高血压，冠状动脉疾病，心力衰竭，中风和周围动脉疾病， 以及代谢疾病（例如糖尿病）中的血管并发症。因此，更好地理解 血管衰老的分子调节可能会提供更大的机会来确定潜在的有希望的目标 预防或延迟血管衰老和与年龄有关的心血管疾病的新型临床干预措施。 当前的应用旨在填补未满足的科学差距，以阐明 血管衰老。血管平滑肌细胞（VSMC）增殖，迁移，矿化，细胞外基质 （ECM）沉积和衰老有助于与年龄相关的血管结构和功能变化。作为 结果，内侧和新内膜厚度增加，动脉刚度，ECM降解和钙化是 血管衰老的表现，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。我们发现关键转录因子Runx2在 依赖年龄的方式，runx2的SMC特异性缺失抑制了血管并发症 在衰老中发音，包括动脉粥样硬化，新内膜形成和血管钙化。此外， VSMC中的Runx2缺乏抑制了VSMC基质蛋白和衰老的表达，这是两个标志 VSMC衰老，支持Runx2在调节其已知功能的血管衰老中的新功能 在调节VSMC钙化中。从机械上讲，我们确定了先前未识别的Runx2振荡 VSMC在体内的培养物以及小鼠动脉中。 VSMC中的Runx2振荡与 关键时钟调节器，BMAL1和时钟调节的FOXO1的振荡。巧合，增加 BMAL1和FOXO1的表达在衰老动脉中被证明，类似于Runx2。使用 功能丧失方法，我们的初步研究进一步证明了昼夜节律的致病功能 （BMAL1）和O-Glcnacylation在调节Runx2表达中。这些结果支持以下假设 时钟节奏和蛋白O-Glcnacylation的相互作用促进了通过 FOXO/RUNX2信号轴。使用新型诱导SMC特异性BMAL1，OGT和RUNX2缺乏动物 该提案模型将表征小鼠昼夜节律调节的血管老化（AIM 1）；并描绘 昼夜节律调节血管衰老的机制（AIM 2）。拟议研究的结果将 开发一种新型的范式血管时钟和O-Glcnacylation的OFFOXO/RUNX2信号传导的调节 血管衰老的轴，这将提高我们对管理血管衰老的基本机制的理解。作为 血管衰老促进许多疾病，本应用中发现的新机制也应具有 广泛的科学和翻译对人类寿命和改善公共卫生的影响。