PPAR gamma regulates vascular endothelial reactive species production in diabetes

PPAR γ 调节糖尿病血管内皮活性物质的产生

• 批准号: 7548578
• 负责人: C MICHAEL HART
• 金额: $ 32.51万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7548578
• 关键词: 2,4-thiazolidinedione; Address; Animal Model; Animals; Arterial Fatty Streak; Arterial Intimas; Atherosclerosis; Attenuated; Biological Availability; Blood Vessels; Cause of Death; Cell Wall; Clinical Research; Cuprozinc Superoxide Dismutase; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diet; Dominant-Negative Mutation; Endothelial Cells; Equilibrium; Event; Functional disorder; Gene Expression; Generations; Goals; Human; Hypertension; In Vitro; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intervention; Knockout Mice; Ligands; Mediating; Mediator of activation protein; Metabolic; Metabolism; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; NADPH Oxidase; Nitric Oxide; Nitrogen; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Oxygen; PPAR gamma; Pathogenesis; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physiology; Play; Post-Translational Protein Processing; Post-Translational Regulation; Prevention; Prevention strategy; Production; Proteins; Regulation; Role; Site; Smooth Muscle Myocytes; Streptozocin; Stroke; Superoxides; Thiazolidinediones; Thick; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; activating transcription factor; animal tissue; diabetic; human NOS3 protein; improved; in vitro activity; in vivo; innovation; intima media; loss of function; macrovascular disease; mortality; non-diabetic; novel; novel strategies; prevent; programs; protective effect

DESCRIPTION (provided by applicant): Vascular disease, including heart attack and stroke, are major causes of death and illness in patients with diabetes. This long term goal of this application is to identify novel strategies to reduce vascular disease in diabetes. The balanced production of reactive nitrogen and oxygen species plays a critical role in the regulation of normal vascular function. Diabetes increases oxidative stress in vascular wall cells leading to reduced nitric oxide (NO) bioavailability and endothelial dysfunction. This proposal explores the novel hypothesis that the ligand-activated transcription factor, peroxisome proliferator-activated receptor gamma (PPARg) controls a program of gene expression in vascular endothelium that regulates the balance between the production of reactive nitrogen and oxygen species and that PPARg stimulation exerts vascular protective effects in vivo by directly stimulating endothelial PPARg to increase NO bioavailability. The PI has demonstrated that direct activation of vascular endothelial cell PPARg with thiazolidinediones increased endothelial cell NO release and reduced superoxide production. Aim 1 will examine mechanisms by which PPARg alters endothelial superoxide metabolism in vitro and in vivo. Preliminary data indicate that PPARg activation decreases the enhanced expression and activity of NADPH oxidase in the vascular wall of diabetic animals and attenuates vascular dysfunction. Aim 2 will define the impact of PPARg activation on post- translational mechanisms regulating eNOS activity in vitro and in vivo. Because PPARg ligands do not increase the expression of endothelial nitric oxide synthase (eNOS), this aim will focus on PPARg-mediated alterations in the post-translational regulation of eNOS activity including eNOS-protein interactions and site- specific eNOS phosphorylation events. Aim 3 will determine basal and thiazolidinedione-stimulated vascular endothelial function in normal and diabetic endothelial-specific PPARg null mice. These innovative studies will clarify the vascular consequences of reduced endothelial PPARg function and permit analysis of specific effects of endothelial PPARg activity in vascular function. This proposal will clarify roles of PPARg in vascular regulation in diabetes and contribute to the development of improved strategies for the prevention and treatment of vascular disease associated with impaired endothelial NO production.

描述（由申请人提供）：血管疾病，包括心脏病发作和中风，是糖尿病患者死亡和患病的主要原因。该应用的长期目标是确定减少糖尿病血管疾病的新策略。活性氮和氧的平衡产生对于正常血管功能的调节起着至关重要的作用。糖尿病会增加血管壁细胞的氧化应激，导致一氧化氮 (NO) 生物利用度降低和内皮功能障碍。该提案探讨了一个新的假设，即配体激活的转录因子、过氧化物酶体增殖物激活受体γ（PPARg）控制血管内皮中的基因表达程序，调节活性氮和氧的产生之间的平衡，并且PPARg刺激发挥作用通过直接刺激内皮 PPARg 增加 NO 生物利用度，发挥体内血管保护作用。 PI 证明，用噻唑烷二酮直接激活血管内皮细胞 PPARg 可增加内皮细胞 NO 的释放并减少超氧化物的产生。目标 1 将研究 PPARg 在体外和体内改变内皮超氧化物代谢的机制。初步数据表明，PPARg 激活可降低糖尿病动物血管壁中 NADPH 氧化酶的增强表达和活性，并减轻血管功能障碍。目标 2 将定义 PPARg 激活对体外和体内调节 eNOS 活性的翻译后机制的影响。由于 PPARg 配体不会增加内皮一氧化氮合酶 (eNOS) 的表达，因此该目标将重点关注 PPARg 介导的 eNOS 活性翻译后调节的改变，包括 eNOS-蛋白质相互作用和位点特异性 eNOS 磷酸化事件。目标 3 将确定正常和糖尿病内皮特异性 PPARg 无效小鼠的基础血管内皮功能和噻唑烷二酮刺激的血管内皮功能。这些创新研究将阐明内皮 PPARg 功能降低的血管后果，并允许分析内皮 PPARg 活性对血管功能的具体影响。该提案将阐明 PPARg 在糖尿病血管调节中的作用，并有助于制定预防和治疗与内皮 NO 生成受损相关的血管疾病的改进策略。