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.

血管钙化和僵硬是糖尿病血管疾病的特征，糖尿病血管疾病是一种常见的心血管疾病 导致退伍军人人群发病率和死亡率增加的并发症。退伍军人事务部 糖尿病试验证明，退伍军人的血管钙化增加，但降脂 他汀类药物未能抑制疾病的进展。生物钟被打乱是军队中常见的问题 人员，这影响到我们的许多退伍军人。昼夜节律异常与 加重了糖尿病心血管疾病。然而，昼夜节律异常在加速中的作用 糖尿病血管病变的发病机制尚不清楚。因此，当前的应用程序旨在了解 糖尿病患者的正常昼夜节律紊乱如何影响血管钙化和僵硬？ 将填补尚未填补的科学空白。糖尿病通常以高血糖和氧化应激为特征， 已知它们可以促进蛋白质O-GlcN酰化，这是一种关键的翻译后蛋白质修饰，调节 无数的细胞过程。我们已经证明，在血管平滑肌细胞(VSMC)中，升高的O- GlcN酰化/AKT/FOXO信号诱导主要钙化因子Runx2的表达，从而 促进VSMC钙化。在初步研究中，我们发现了Runx2的时间振荡 与关键的昼夜节律调节因子BMAL1一起在体内和体外的小鼠主动脉和VSMC中表达。在……里面 糖尿病小鼠动脉，O-GlcN酰化升高和BMAL1表达增加，这是 与Runx2的上调有关。此外，利用BMAL1缺陷的VSMC，我们确定了一个 BMAL1依赖信号对VSMC O-GlcN酰化的致病调控因此，我们假设 异常昼夜节律通过O-GlcN酰化促进糖尿病患者的血管钙化- 调节的FOXO/Runx2信号轴。使用我们新生成的可诱导的SMC特异性OGT和BMAL1 删除小鼠模型，该提案将揭示血管生物钟和O-O-1的新致病作用 GlcN酰化在调节糖尿病血管钙化中的作用；并描绘了潜在的分子 机制。拟议研究的结果将增进我们对基本 糖尿病血管钙化的发病机制，这应该提供重要的 对开发成功的血管疾病治疗方法的临床意义的分子洞察 生物钟异常和O-GlcN酰化增加。