PPAR gamma regulates vascular endothelial reactive species production in diabetes

项目摘要/摘要 血管疾病，包括心脏病发作和中风，是患者死亡和疾病的主要原因 糖尿病。这项应用的长期目标是确定减少血管疾病的新策略 糖尿病。活性氮和氧物种的平衡生产在 调节正常的血管功能。糖尿病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。这项提议探讨了这部小说 假设配体激活的转录因子，过氧化物酶体增殖物激活的受体伽马 (PPARG)控制血管内皮细胞基因表达的程序，该程序调节 活性氮和氧的产生及PPARg刺激对血管的保护作用 通过直接刺激内皮细胞PPARg增加NO的生物利用度而产生体内效应。少年派有 结果表明，噻唑烷二酮类化合物对血管内皮细胞PPARg的直接激活作用增强 内皮细胞NO释放减少，超氧化物生成减少。目标1将检查通过哪些机制 PPARG在体内外改变内皮细胞超氧化物代谢。初步数据表明，PPARg 活化降低糖尿病大鼠血管壁NADPH氧化酶的表达和活性 并减轻血管功能障碍。目标2将定义PPARg激活对POST-2的影响 体内外调节eNOS活性的翻译机制。因为PPARg配体不会 增加内皮型一氧化氮合酶(ENOS)的表达，这一目标将集中在PPARg介导的 内皮型一氧化氮合酶活性的翻译后调节的改变，包括内皮型一氧化氮合酶-蛋白质相互作用和 位点特异性eNOS磷酸化事件。目标3将确定基础血管和噻唑烷二酮刺激的血管 正常和糖尿病内皮特异性PPARg缺失小鼠的内皮功能。这些创新的研究将 阐明内皮细胞PPARg功能降低的血管后果，并允许分析特定的 内皮细胞PPARg活性对血管功能的影响这项提议将阐明PPARg在血管中的作用 对糖尿病的监管，并有助于制定更好的预防和治疗策略 治疗与内皮一氧化氮产生受损相关的血管疾病。

Project Summary / Abstract Vacular 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.