Circadian regulation of vascular aging

血管老化，血管中与年龄相关的分子、结构和功能的变化，而不是 不仅会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、冠心病、心力衰竭、中风和外周动脉疾病，如 以及代谢性疾病的血管并发症，如糖尿病。因此，更好地理解 血管衰老的分子调控可能为发现潜在的潜在靶点提供更大的机会 预防或延缓血管老化和年龄相关心血管疾病的新型临床干预措施。 目前的应用旨在填补尚未填补的科学空白，以阐明 血管老化。血管平滑肌细胞(VSMC)增殖、迁移、矿化、细胞外基质 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。作为一名 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，这会促进包括动脉粥样硬化在内的心血管疾病， 高血压、血管钙化和中风。我们发现一个关键的转录因子Runx2在一个 年龄依赖的方式和SMC特异性的Runx2缺失抑制了更多的血管并发症 明显的衰老，包括动脉粥样硬化、新生内膜形成和血管钙化。此外， VSMC缺乏Runx2抑制VSMC基质蛋白的表达和衰老，这是VSMC的两个特征 VSMC衰老，支持Runx2在调节血管衰老方面的新功能，这是其已知功能之外的 在调节VSMC钙化中起重要作用。从机制上讲，我们发现了一种以前未发现的Runx2振荡 培养的VSMC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和时钟调节器FOXO1的振荡。巧合的是，增加了 BMAL1和FOXO1在衰老的动脉中表达，与Runx2相似。通过使用 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作用。 (BMal1)和O-GlcN酰化在调节Runx2表达中的作用这些结果支持这样的假设： 生物钟节律和蛋白质O-GlcN酰化的相互作用通过 FOXO/Runx2信号轴。利用新型可诱导的SMC特异性BMAL1、OGT和Runx2缺陷动物 模型，该提案将表征昼夜节律调节的小鼠血管衰老(目标1)；并描绘 血管衰老的昼夜节律机制(目标2)。拟议研究的结果将 在FOXO/Runx2信号的血管时钟和O-GlcN酰化调控下建立新的范式 AXIS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。AS 血管老化促进了许多疾病，在这一应用中发现的新机制也应该具有 在延长人类寿命和改善公共健康方面产生广泛的科学和转化影响。

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.