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Molecular Regulation of Vascular Calcification in Diabetes

糖尿病血管钙化的分子调控

基本信息

批准号：
10421252
负责人：
Yabing Chen
金额：
--
依托单位：
BIRMINGHAM VA MEDICAL CENTER
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：
2019-10-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10421252
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 Post-Translational Protein Processing Prevention therapy Proteins Proteomics Proto-Oncogene Proteins c-akt Regulation Reporting Role Signal Transduction Smooth Muscle Myocytes Streptozocin Time United States Department of Veterans Affairs Up-Regulation Vascular Diseases Vascular Smooth Muscle Vascular calcification Veterans calcification circadian circadian pacemaker circadian regulation diabetic diabetic cardiomyopathy feeding improved in vivo insight military veteran mortality mouse model novel novel strategies novel therapeutics tool

项目摘要

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标志，一种普遍的心血管疾病