Vascular complications of type 2 diabetes: tyrosine phosphorylation of the endothelial nitric oxide synthase (eNOS)

2 型糖尿病的血管并发症：内皮一氧化氮合酶 (eNOS) 的酪氨酸磷酸化

• 批准号: 165772555
• 负责人: Professorin Dr. Ingrid Fleming, Ph.D.
• 金额: --
• 依托单位: Department of Biotechnology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/165772555?language=en
• 关键词: Vascular; complications; type; diabetes; tyrosine

Up to 80% of deaths in patients with diabetes are due to the associated cardiovascular complications. Endothelial dysfunction is an early event in disease development and is characterised by the decreased production of endothelium-derived nitric oxide (NO). This not only affects vascular tone and homeostasis but also results in the impaired mobilization of progenitor cells from the bone marrow. The activity of the endothelial NO synthase (eNOS) is regulated by Ca2+-dependent and –independent processes; particularly by its posttranslational modification by phosphorylation. We have recently identified a novel regulatory tyrosine residue within eNOS (Tyr657) that attenuates enzyme activity and linked this event with the activation of the redox- and insulin-sensitive tyrosine kinase, Pyk2. This proposal aims to determine the extent to which Pyk2 activation and eNOS Tyr657 phosphorylation underlies the vasculopathy associated with diabetes. Moreover as eNOS determines the restorative capacity of circulating progenitor cells as well as their mobilization from the bone marrow niche, we plan to assess the role of Pyk2 and tyrosine phosphatases in regulating the angiogenic potential of healthy and diabetic progenitor cells as well as the mobilization of these cells from the bone marrow, again under control and diabetic conditions. Studies in animal models will be complemented by studies on human cells isolated from healthy and diabetic patients. The organisation of the project makes optimal use of the expertise available at the two locations and there is a clear synergy expected by the close collaboration of the two groups.

高达80%的糖尿病患者的死亡是由于相关的心血管并发症。内皮功能障碍是疾病发展的早期事件，其特征在于内皮源性一氧化氮（NO）的产生减少。这不仅影响血管张力和体内平衡，而且还导致骨髓祖细胞动员受损。内皮型一氧化氮合酶（eNOS）的活性受钙离子依赖性和非依赖性过程的调节，特别是通过磷酸化进行翻译后修饰。我们最近已经确定了一种新的调节酪氨酸残基eNOS（Tyr657），减弱酶的活性，并连接这一事件与氧化还原和胰岛素敏感的酪氨酸激酶，Pyk2的激活。该提案旨在确定Pyk2激活和eNOS Tyr657磷酸化在多大程度上是糖尿病相关血管病变的基础。此外，由于eNOS决定了循环祖细胞的恢复能力以及它们从骨髓龛中的动员，我们计划再次在对照和糖尿病条件下评估Pyk 2和酪氨酸磷酸酶在调节健康和糖尿病祖细胞的血管生成潜力以及这些细胞从骨髓中的动员中的作用。动物模型的研究将通过从健康和糖尿病患者中分离的人类细胞的研究来补充。该项目的组织充分利用了两个地点现有的专门知识，预计两个小组的密切合作将产生明显的协同作用。

项目成果

Monoamine Oxidases Are Mediators of Endothelial Dysfunction in the Mouse Aorta

单胺氧化酶是小鼠主动脉内皮功能障碍的介质

• DOI: 10.1161/hypertensionaha.113.01314
• 发表时间: 2013
• 期刊: Hypertension
• 影响因子: 8.3
• 作者: Sturza A;Leisegang M;Babelova A;Schröder K;Benkhoff S;Loot AE;Fleming I;Schulz R;Muntean D;Brandes RP
• 通讯作者: Brandes RP

Leptin Potentiates Endothelium-Dependent Relaxation by Inducing Endothelial Expression of Neuronal NO Synthase

• DOI: 10.1161/atvbaha.112.251140
• 发表时间: 2012-07-01
• 期刊: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
• 影响因子: 8.7
• 作者: Benkhoff, Sebastian;Loot, Annemarieke E.;Schroeder, Katrin
• 通讯作者: Schroeder, Katrin