Circadian regulation of vascular aging

血管衰老的昼夜节律调节

基本信息

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
项目类别：
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&apos 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

项目摘要

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，即与年龄相关的血管分子、结构和功能的变化，而不是不仅损害正常的血管收缩和顺应性，还会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（例如糖尿病）的血管并发症。因此，更好地了解血管老化的分子调控可能为识别潜在的有希望的靶标提供更多机会预防或延缓血管衰老和与年龄相关的心血管疾病的新型临床干预措施。目前的应用旨在填补未满足的科学空白，以阐明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。作为一个结果，增加了内侧和新内膜厚度、动脉僵硬度、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。我们发现关键转录因子 Runx2 在年龄依赖性方式，SMC 特异性删除 Runx2 可抑制血管并发症衰老过程中明显，包括动脉粥样硬化、新内膜形成和血管钙化。此外， VSMC 中的 Runx2 缺陷会抑制 VSMC 基质蛋白的表达和衰老，这是 VSMC 的两个标志 VSMC 老化，支持 Runx2 调节血管老化的新功能，该功能超出了其已知功能调节 VSMC 钙化。从机制上讲，我们发现了以前未被识别的 Runx2 振荡培养物以及体内小鼠动脉中的 VSMC。 VSMC 中的 Runx2 振荡与关键时钟调节器 BMAL1 和时钟调节 FOXO1 的振荡。无独有偶，增加了 BMAL1 和 FOXO1 的表达在老化动脉中得到证实，与 Runx2 的表达相似。随着使用通过功能丧失方法，我们的初步研究进一步证明了生物钟的致病功能 (BMAL1) 和 O-GlcNAcylation 调节 Runx2 表达。这些结果支持以下假设：生物钟节律和蛋白质 O-GlcNAc 酰化的相互作用通过 FOXO/Runx2 信号轴。使用新型诱导型 SMC 特异性 BMAL1、OGT 和 Runx2 缺陷动物模型，该提案将描述小鼠生物钟调节的血管衰老的特征（目标 1）；并划定血管衰老的昼夜节律调节机制（目标 2）。拟议研究的结果将开发一种基于血管时钟和 FOXO/Runx2 信号传导的 O-GlcNAcylation 调节的新范例血管衰老的轴，这将增进我们对血管衰老基本机制的理解。作为血管老化会促进许多疾病，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共卫生具有广泛的科学和转化影响。