Pharmacological Restoration of Diabetic Vascular Dysfunction

糖尿病血管功能障碍的药理恢复

• 批准号: 8811828
• 负责人: JANE E REUSCH
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811828
• 关键词: Address; Affect; Antioxidants; Autophagocytosis; Biogenesis; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell Proliferation; Cells; Clinical; Complex; Data; Deoxyglucose; Diabetes Mellitus; Diabetic Angiopathies; Diet; Dipeptidyl Peptidases; Endothelial Cells; Equilibrium; Exercise; Fatty acid glycerol esters; Glucose; Goals; Homeostasis; Human; Hyperglycemia; Impairment; In Vitro; Intervention; Mediating; Mitochondria; Mitochondrial Proteins; Modeling; Modification; Morbidity - disease rate; Mus; Nitric Oxide; Nitric Oxide Synthase; Nutrient; Oxidants; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Population; Process; Production; Publishing; Pyruvaldehyde; Randomized; Rattus; Reactive Oxygen Species; Regulation; Relative (related person); Reporting; Respiration; Risk Factors; Risk Reduction; Role; Running; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stress; Structure; Testing; Therapeutic; Vascular Diseases; Veterans; cardiovascular disorder risk; cardiovascular risk factor; deprivation; diabetic; diabetic rat; fitness; genetic approach; glucagon-like peptide; improved; in vivo; inhibitor/antagonist; insulin secretion; macrovascular disease; male; mitochondrial dysfunction; mortality; mouse model; new therapeutic target; novel; novel strategies; novel therapeutics; protein expression; public health relevance; research study; response; restoration; therapeutic target; treatment duration; vasomotion

Problem: Diabetes (DM) increases cardiovascular (CV) and all-cause mortality despite aggressive risk factor modification. Our long term goal is to define novel targets for cardiovascular risk reduction in diabetes. Vascular mitochondria are a potential new target. Mitochondria regulate endothelial function and smooth muscle cell (SMC) proliferation and mitochondrial dysfunction is a hallmark of diabetes. Exercise elicits an adaptive improvement in mitochondrial quality in healthy vessels; this response is absent in diabetes. The question addressed in this proposal is whether pharmacological targeting of eNOS and SIRT with glucagon- like peptide 1 (GLP-1) can restore signaling to mitochondrial biogenesis and improve mitochondrial dynamics and vascular function. GLP-1 is a diabetes medication that also induces eNOS, SIRT1, mitochondrial biogenesis and autophagy 21. New preliminary data suggest that saxagliptin (SAXA), a dipeptidyl peptidase-4 inhibitor that increases circulating endogenous GLP-1, restores induction of eNOS and mitochondrial protein expression with exercise in DM and improves running distance. Hypotheses: Abnormal mitochondrial function and impaired stress mediated mitochondrial dynamics in the diabetic vasculature will be improved by GLP-1 via eNOS and SIRT1 signaling. SA #1: What is the impact of GLP-1 on vascular mitochondrial adaptation in DM? Rationale: Control rats subjected to 8 day exercise show increased activation of the mitochondrial biogenesis, improved mitochondrial function plus increased fusion and decreased fission. We will examine the impact of GLP-1 on vascular mitochondrial function and turnover in diabetes and use targeted deletion of eNOS, endothelial cell (EC) SIRT1, SMC SIRT1 with or without exercise to test mitochondrial homeostatic adaptation in vivo. Hypothesis 1.1: Intervention with GLP-1 will improve mitochondrial function through augmentation of vascular mitochondrial adaptation (biogenesis, fusion and autophagy) to exercise in high fat induced diabetes. Hypothesis 1.2: eNOS and/or SIRT1 are required for GLP-1 rescue of mitochondrial adaptation. Approach: 1a. Male C57BL6 on chow versus high fat (HF) diet for 10 weeks will be randomized to GLP-1 or vehicle with or without exercise for 8 days. 1b. c57eNOS -/- and c57b eNOS +/+ will be treated as in SA1a. 1c. c57 mice with EC or SMC deletion of SIRT1 and controls will be treated as in SA1a. These experiments will clarify the importance of eNOS and SIRT1 for vascular mitochondrial adaptation to exercise in vivo and define the impact of diabetes and GLP-1 on these pathways. SA #2: How does diabetes affect dynamic mitochondrial adaptation in vascular cells in vitro? Rationale: Regulation of mitochondrial function requires a complex interplay between mitochondrial biogene- sis and remodeling through fission, fusion and autophagy. Hypothesis 2.1: Endothelial cells and/or smooth muscle cells from DM models will have impaired mitochondrial dynamics. Hypothesis 2.2: GLP-1 will improve mitochondrial function and dynamics in DM cells through eNOS and/or SIRT. Approach: These experiments will examine the impact of DM and GLP-1 on mitochondrial quality and dynamics in vitro and employ genetic approaches to define the relative contribution of eNOS and SIRT for mitochondrial quality in vascular cells. Impact on the Veteran Population: Mitochondrial dynamics are a novel target to decrease excess CV risk in diabetes. Interventions targeting mitochondrial ROS have been consistently ineffective in human studies. Our observation that 8 days of treatment with SAXA restores vascular induction of mitochondrial biogenesis provides proof of concept that impaired vascular mitochondrial adaptation is targetable with a currently available drug. Pharmacological restoration of mitochondrial dynamics in diabetes could have implications for macrovascular and microvascular complications of diabetes.

问题：糖尿病（DM）增加了心血管（CV）和全因死亡率，尽管风险有侵略性 因子修改。我们的长期目标是定义糖尿病心血管风险降低的新目标。 血管线粒体是潜在的新靶标。线粒体调节内皮功能和光滑 肌肉细胞（SMC）增殖和线粒体功能障碍是糖尿病的标志。运动引起 健康血管中线粒体质量的适应性改善；这种反应在糖尿病中不存在。这 该提案中解决的问题是用胰高血糖素对eNOS和SIRT的药理靶向 - 像肽1（GLP-1）一样，可以将信号恢复到线粒体生物发生并改善线粒体动力学 和血管功能。 GLP-1是一种糖尿病药物，也诱导eNOS，SIRT1，线粒体 生物发生和自噬21。新的初步数据表明saxagliptin（saxa），二肽基肽酶-4 增加循环内源性GLP-1的抑制剂，恢复eNOS和线粒体蛋白的诱导 在DM中进行运动表达并改善跑步距离。 假设：线粒体功能异常和应力受损的线粒体 GLP-1通过eNOS和SIRT1信号传导将改善糖尿病脉管系统中的动力学。 SA＃1：GLP-1对DM血管线粒体适应的影响是什么？ 理由：接受8天运动的对照大鼠显示线粒体生物发生的激活增加， 线粒体功能的改善加上融合和裂变降低。我们将研究GLP-1的影响 关于糖尿病的血管线粒体功能和周转，并使用eNOS的靶向缺失，内皮细胞 （EC）SIRT1，SMC SIRT1带有或不运动以在体内测试线粒体稳态适应。 假设1.1：与GLP-1的干预将通过增加血管来改善线粒体功能 线粒体适应性（生物发生，融合和自噬）在高脂肪诱导的糖尿病中运动。 假设1.2：eNOS和/或SIRT1是GLP-1拯救线粒体适应所必需的。方法： 1a。雄性C57BL6在Chow与高脂饮食（HF）饮食10周的雄性C57BL6将随机分为GLP-1或使用 或不运动8天。 1B。 C57ENOS - / - 和C57B ENOS +/ +将被视为SA1A。 1C。 C57小鼠 SIRT1的EC或SMC删除和对照将被视为SA1A。这些实验将阐明 eNOS和SIRT1对于血管线粒体适应的重要性，在体内运动并定义影响 这些途径上的糖尿病和GLP-1。 SA＃2：糖尿病在体外如何影响血管细胞的动态线粒体适应？ 理由：线粒体功能的调节需要线粒体biogen-之间的复杂相互作用 通过裂变，融合和自噬进行SIS和重塑。假设2.1：内皮细胞和/或平滑 来自DM模型的肌肉细胞将损害线粒体动力学。假设2.2：GLP-1将改善 通过eNOS和/或SIRT在DM细胞中的线粒体功能和动力学。方法：这些实验 将检查DM和GLP-1对线粒体质量和体外动态的影响，并采用遗传 定义eNOS和SIRT在血管细胞中线粒体质量的相对贡献的方法。 对退伍军人人口的影响：线粒体动力学是减少过量CV的新目标 糖尿病的风险。靶向线粒体ROS的干预措施在人类中一直无效 研究。我们观察到8天的萨克斯治疗恢复了线粒体的血管诱导 生物发生提供了概念证明，表明受损的血管线粒体适应性是针对性的 使用当前可用的药物。糖尿病中线粒体动力学的药理恢复可以 对糖尿病的大血管和微血管并发症有影响。