Molecular Regulation of Vascular Calcification in Diabetes

糖尿病血管钙化的分子调控

• 批准号: 9775753
• 负责人: Yabing Chen
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9775753
• 关键词: ARNTL gene; Affect; Animal Model; Animals; Aorta; Arteries; Blood Vessels; Cardiovascular system; Cell physiology; Circadian Dysregulation; Circadian Rhythms; Clinical; Complication; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Disease Progression; Dose; Echocardiography; FOXO1A gene; Genes; Health; High Fat Diet; Hyperglycemia; In Vitro; Knowledge; Lipids; Mass Spectrum Analysis; Mediating; Military Personnel; Molecular; Morbidity - disease rate; Mus; Outcome; Outcome Study; Oxidative Stress; Pathogenesis; Pathologic; Physiological; Population; Post-Translational Protein Processing; Prevention therapy; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Regulation; Reporting; Role; Signal Transduction; Smooth Muscle Myocytes; Streptozocin; Time; Up-Regulation; Vascular Diseases; Vascular Smooth Muscle; Vascular calcification; Veterans; calcification; circadian; circadian pacemaker; circadian regulation; diabetic; diabetic cardiomyopathy; feeding; improved; in vivo; insight; mortality; mouse model; novel; novel strategies; novel therapeutics; tool

Vascular calcification and stiffness are hallmarks of diabetic vascular disorder, a prevalent cardiovascular complication that leads to increased morbidity and mortality in the Veteran's population. The Veterans Affairs Diabetes Trial has documented that vascular calcification was elevated in the Veterans, but the lipid-lowering statins failed to inhibit the disease progression. Disrupted circadian clock is a common issue in military personnel, which affects many of our Veterans. Abnormal circadian rhythm has been associated with exacerbated diabetic cardiovascular disease. However, the role of abnormal circadian rhythm in accelerating pathogenesis of diabetic vascular disease is not clear. Therefore, the current application aims to understand how disruption of normal circadian rhythms may affect vascular calcification and stiffness in diabetes, which would fill the unmet scientific gaps. Diabetes is often featured with both hyperglycemia and oxidative stress, which are known to promote protein O-GlcNAcylation, a key posttranslational protein modification that regulates numerous cellular processes. We have shown that in vascular smooth muscle cells (VSMC), elevated O- GlcNAcylation/AKT/FOXO signaling induces the expression of the master calcification factor, Runx2, thus promoting VSMC calcification. In preliminary studies, we uncovered a time-of-day oscillation of Runx2 expression along with BMAL1, the key circadian regulator, in mouse aortas in vivo and in VSMC in vitro. In diabetic mouse arteries, elevation of O-GlcNAcylation and increased expression of BMAL1 were identified, which was associated with upregulation of Runx2. Furthermore, using BMAL1 deficient VSMC, we determined a causative regulation of O-GlcNAcylation in VSMC by BMAL1-dependent signals. Therefore, we hypothesize that “Abnormal circadian rhythm promotes vascular calcification in diabetes through O-GlcNAcylation- regulated FOXO/Runx2 signaling axis.” With our newly generated inducible SMC-specific OGT and BMAL1 deletion mouse models, the proposal will uncover a novel causative role of vascular circadian clock and O- GlcNAcylation in regulating vascular calcification in diabetes; and delineate the underlying molecular mechanisms. Outcomes from the proposed studies will advance our knowledge in understanding of the basic mechanisms underlying pathogenesis of vascular calcification in diabetes, which should provide important molecular insights into clinical implications in the developing successful therapy for vascular disease featuring abnormal circadian clock and increased O-GlcNAcylation.

血管钙化和刚度是糖尿病血管疾病的标志，这是一种普遍的心血管疾病 并发症导致退伍军人人口的发病率和死亡率增加。退伍军人事务 糖尿病试验记录了退伍军人的血管钙化升高，但降低脂质的钙化 他汀类药物未能抑制疾病进展。昼夜节律破坏是军事中的一个常见问题 人员，影响我们许多退伍军人。昼夜节律异常与 恶化的糖尿病心血管疾病。但是，昼夜节律异常在加速中的作用 糖尿病血管疾病的发病机理尚不清楚。因此，当前的申请旨在了解 正常的昼夜节律的破坏如何影响糖尿病的血管钙化和僵硬，这 会填补未满足的科学空白。糖尿病通常具有高血糖和氧化应激， 已知可以促进蛋白质O-Glcnacylation，这是一种调节的关键翻译后蛋白质修饰 许多细胞过程。我们已经表明，在血管平滑肌细胞（VSMC）中，O-升高 glcnacylation/akt/foxo信号传导诱导主钙化因子Runx2的表达，因此 促进VSMC计算。在初步研究中，我们发现了runx2的一天振荡 与BMAL1，关键的昼夜节律调节剂，体内小鼠主动脉和VSMC的体外表达。 鉴定了糖尿病小鼠动脉，O-Glcnacylation的升高和BMAL1表达的增加，这 与Runx2的上调有关。此外，使用BMAL1缺陷VSMC，我们确定了一个 BMAL1依赖性信号在VSMC中对O-Glcnacylation的病因调节。因此，我们假设 “异常昼夜节律通过O-Glcnacylation-促进糖尿病的血管计算 - 受调节的FOXO/runx2信号轴。 删除小鼠模型，该提案将发现血管昼夜时钟和O-的新型致病作用 在调节糖尿病的血管计算中的Glcnacylation；并描绘基础分子 机制。拟议研究的结果将促进我们在理解基本的知识 糖尿病中血管计算的发病机理的基础机制，应提供重要的 分子见解对发展的成功治疗血管疾病的临床意义的见解 昼夜节律异常，O-Glcnacylation增加。