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Functional role of Angiopoietin-2 in diabetic heart

血管生成素-2 在糖尿病心脏中的功能作用

基本信息

批准号：
7232452
负责人：
JIAN-XIONG CHEN
金额：
$ 18.62万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-15 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7232452
关键词：
Affect Agonist Angiogenic Factor Angiopoietin-1 Angiopoietin-2 Angiopoietins Animal Model Apoptosis Atherosclerosis Attenuated Cell Proliferation Cell Survival Client Clinical Research Coronary Coronary artery Data Development Diabetes Mellitus Diabetic mouse Disease regression Endothelial Cells Endothelium Exposure to Family suidae Functional disorder Glucose Growth Heart Heat-Shock Proteins 90 Hyperglycemia Immigration Impairment In Vitro Lead Ligands Mediating Molecular Mus Myocardial Myocardial Infarction Nitric Oxide Pathway interactions Patients Pericytes Personal Satisfaction Play Production Proteins Publishing Receptor Protein-Tyrosine Kinases Research Design Research Personnel Retinal Role Signal Transduction Signaling Protein Testing Tumor Angiogenesis Up-Regulation Vascular Endothelial Growth Factors angiogenesis base cell motility diabetic human NOS3 protein in vivo mortality mouse model novel novel therapeutics prevent programs receptor survivin

项目摘要

DESCRIPTION (provided by applicant): In patients with diabetes mellitus, coronary collateral growth and myocardial angiogenesis are significantly impaired, and these may contribute to high mortality in diabetic myocardial infarction. Diabetic impaired angiogenesis is strongly associated with hyperglycemia-induced endothelial cell apoptosis and angiogenic factors signal transduction dysfunction such as VEGF and eNOS/NO signaling. Tie-2 is an endothelial- specific receptor tyrosine kinase. Angiopoietin-1 (Ang-1, agonist) and angiopoietin-2 (Ang-2, antagonist) are the two key ligands of Tie-2 receptor. Ang-1 has been shown to play a critical role in regulating endothelial cell survival and pericytes recruitment, whereas Ang-2 has been identified as a vessel-destabilizing agent that plays a predominant role in controlling angiogenesis or vessel regression. Recent studies reveal that Ang-2 is abnormally raised both in animal models and in diabetic patients. Further, hyperglycemia-induced Ang-2 contributes to pericytes loss in diabetic retinal vasculature. So far, little is known about the functional consequences of hyperglycemia-induced Ang-2 on diabetic myocardial endothelium. Our preliminary data reveals that exposure to high glucose increases Ang-2 expression and blocks Ang-1-induced myocardial endothelial cell migration indicating that an abnormality of Ang-2 has a detrimental effect on diabetic myocardial angiogenesis. Previously, we made a novel observation that Ang-1 stimulates angiogenesis via upregulation of heat shock protein 90 (Hsp90)/eNOS interaction in porcine coronary artery endothelial cells. Therefore, we propose that hyperglycemia-induced Ang-2 disrupts Ang-1/Hsp90 client protein interactions and contributes to myocardial endothelium destabilization and impairment of myocardial angiogenesis. To explore our notion, using db/db diabetic mice model, we will examine whether: (1) Hyperglycemia-induced Ang-2 disrupts Ang-1 mediated Hsp90/client protein interactions, leads to myocardial endothelium apoptosis and destabilization, loss of pericytes and impairment of angiogenesis; and (2) Pretreatment with Ang-1 prevents hyperglycemia-induced myocardial endothelial apoptosis and destabilization via promoting Hsp90/client protein interactions and recruitment of pericytes. Our proposed studies will elucidate important and novel mechanisms underlying hyperglycemia-induced impairment of angiogenesis and should provide a framework for developing new therapeutic strategies for the treatment of diabetic abnormal angiogenesis.

描述（申请人提供）：在糖尿病患者中，冠状动脉侧枝生长和心肌血管生成显着受损，这些可能导致糖尿病性心肌梗死的高死亡率。糖尿病血管生成受损与高血糖诱导的内皮细胞凋亡和血管生成因子信号转导功能障碍（例如 VEGF 和 eNOS/NO 信号传导）密切相关。 Tie-2 是一种内皮特异性受体酪氨酸激酶。血管生成素-1（Ang-1，激动剂）和血管生成素-2（Ang-2，拮抗剂）是Tie-2受体的两个关键配体。 Ang-1 已被证明在调节内皮细胞存活和周细胞募集中发挥关键作用，而 Ang-2 已被确定为血管不稳定剂，在控制血管生成或血管退化中发挥主要作用。最近的研究表明，Ang-2 在动物模型和糖尿病患者中均异常升高。此外，高血糖诱导的 Ang-2 会导致糖尿病视网膜血管系统中周细胞的损失。迄今为止，关于高血糖诱导的 Ang-2 对糖尿病心肌内皮的功能影响知之甚少。我们的初步数据显示，暴露于高葡萄糖会增加 Ang-2 的表达并阻止 Ang-1 诱导的心肌内皮细胞迁移，表明 Ang-2 的异常对糖尿病心肌血管生成具有不利影响。此前，我们发现 Ang-1 通过上调猪冠状动脉内皮细胞中的热休克蛋白 90 (Hsp90)/eNOS 相互作用来刺激血管生成。因此，我们认为高血糖诱导的 Ang-2 会破坏 Ang-1/Hsp90 客户蛋白相互作用，并导致心肌内皮不稳定和心肌血管生成受损。为了探索我们的观点，我们将使用 db/db 糖尿病小鼠模型来检查是否：（1）高血糖诱导的 Ang-2 破坏 Ang-1 介导的 Hsp90/客户蛋白相互作用，导致心肌内皮细胞凋亡和不稳定、周细胞损失和血管生成受损； (2) Ang-1 预处理通过促进 Hsp90/客户蛋白相互作用和周细胞募集来防止高血糖诱导的心肌内皮细胞凋亡和不稳定。我们提出的研究将阐明高血糖引起的血管生成受损的重要且新颖的机制，并为开发治疗糖尿病异常血管生成的新治疗策略提供框架。