Influence of high glucose on endothelial function

高糖对内皮功能的影响

• 批准号: 8492086
• 负责人: SUMATHY MOHAN
• 金额: $ 31.38万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492086
• 关键词: Accounting; Address; Animal Model; Arginine; Arterial Fatty Streak; Arterial Injury; Arteries; Atherosclerosis; Attenuated; Binding; Biological Assay; Biological Availability; Blood Vessels; Cell Culture Techniques; Cell physiology; Clinical; Complement; Diabetes Mellitus; Diabetic mouse; Dimensions; Endothelial Cells; Endothelium; Endothelium-Dependent Relaxing Factors; Event; Focal Adhesion Kinase 1; Focal Adhesions; Foundations; Functional disorder; Generations; Genetic; Genetic Transcription; Glucose; Goals; Healed; Health; Heat shock proteins; Heat-Shock Proteins 90; IKBKB; In Vitro; Injury; Insulin-Dependent Diabetes Mellitus; Integrins; Knowledge; Lead; Lesion; Life; Link; Living Standards; Localized Disease; Mediating; Mediator of activation protein; Metabolic; Modality; Molecular; Molecular Chaperones; Morbidity - disease rate; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Signaling Pathway; Outcome; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Physiological; Play; Procedures; Production; Relaxation; Risk Factors; Role; Severities; Signal Pathway; Signal Transduction; Site; Superoxides; Supplementation; Therapeutic; Variant; Vascular Endothelial Cell; base; cell motility; clinical practice; cofactor; diabetic; diabetic patient; early onset; enzyme substrate; experience; healing; hemodynamics; human NOS3 protein; improved; in vivo; inhibitor/antagonist; innovation; migration; mortality; mouse model; novel; prevent; repaired; response; shear stress; type I diabetic

DESCRIPTION (provided by applicant): Identifying and intervening molecular pathways that directly contribute to vascular complications will have a significant clinical impact in preventing insulin dependent diabetes mellitus (IDDM)-associated vascular complications. We hypothesize that impaired physiological repair mechanisms due to altered endothelium- derived relaxation factor (nitric oxide) signaling pathway mediated by sustained high glucose is responsible for vascular complications. Under normal physiological condition, interaction of heat shock protein (Hsp-86) with endothelial nitric oxide synthase (NOS III) is responsible for nitric oxide-dependent endothelial functions. However, under high glucose condition, there is an enhanced inhibitor kB kinase activity (IKK-2), which competes out NOS lll from binding to Hsp-86. Further IKK-2 binding phosphorylates Hsp-86. This sequence of events lead to inadequate availability of Hsp-86 to NOS III, which decelerates NOS lll activity with a final outcome of integrin-focal adhesion disassembly, delayed endothelial migration and poor vascular repair. Blocking IKK-2 with genetic or pharmacological inhibitors in combination with agents, which are already in clinical practice, may open new avenues to improve nitric oxide production and reduce vascular damage in IDDM patients. The proposed study constitutes innovative approaches with the use of in vitro cell culture based assays using mammalian aortic endothelial cells. Use of genetically-induced diabetic animal model and optimized arterial injury procedures further complement the in vitro mechanistic approach. The specific aims are: Aim 1 will investigate the competitive cross talk between NOS III and IKK-2 with Hsp-86 under the influence of high glucose. The effect of sequentially altered nitric oxide signaling pathway on endothelial migration will be evaluated. Aim 2 will determine in vivo, the contribution of Hsp-86 - IKK-2 cross talk in NOS lll dysregulation in Type-1 mouse model. Aim 3 will evaluate the potentials of blocking IKK-2 independently or in combination with L-arginine in improving endothelial repair mechanism in response to arterial injury. The knowledge gained will help to identify new avenues that will improve the current treatment modalities aimed to prevent or minimize the severity of vascular complications of IDDM patients.

描述(申请人提供)：识别和干预直接导致血管并发症的分子通路将对预防血管并发症产生重大的临床影响。 胰岛素依赖型糖尿病(IDDM)相关血管并发症。我们推测，持续高糖介导的内皮衍生松弛因子(NO)信号通路改变导致的生理修复机制受损是血管并发症的原因。在正常生理条件下，热休克蛋白(HSP-86)与内皮型一氧化氮合酶(NOSIII)的相互作用对一氧化氮依赖的内皮功能起重要作用。然而，在高糖条件下，抑制因子kB激酶活性(IKK-2)增强，从而竞争NOS11与HSP-86的结合。此外，IKK-2结合使HSP-86磷酸化。这一系列事件导致HSP-86对NOS III的可用性不足，从而降低了NOS 111的活性，最终导致整合素局灶性黏附解体、内皮细胞迁移延迟和血管修复不良。用基因或药物抑制剂结合已在临床应用的药物来阻断IKK-2，可能会为改善IDDM患者一氧化氮的产生和减少血管损伤开辟新的途径。这项拟议的研究通过使用哺乳动物主动脉内皮细胞的体外细胞培养分析，构成了创新的方法。使用遗传诱导的糖尿病动物模型和优化的动脉损伤程序进一步补充了体外机制方法。具体目的是：目的1研究高糖影响下NOS III和IKK-2与HSP-86之间的竞争性串扰。将评估顺序改变的一氧化氮信号通路对内皮细胞迁移的影响。目的2在体内研究HSP-86-IKK-2串扰在1型小鼠一氧化氮合酶失调中的作用。目的3评价单独或与L精氨酸联合阻断IKK-2在改善动脉损伤后内皮修复机制中的作用。所获得的知识将有助于确定新的途径，改进目前旨在预防或尽量减少IDDM患者血管并发症严重程度的治疗方式。