Functional role of Angiopoietin-2 in diabetic heart

描述（由申请人提供）：糖尿病患者冠状动脉侧枝生长和心肌血管生成明显受损，这可能导致糖尿病性心肌梗死的高死亡率。糖尿病血管生成障碍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（如VEGF和eNOS/NO信号转导）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 （ang1，激动剂）和血管生成素-2 （ang2，拮抗剂）是Tie-2受体的两种关键配体。Ang-1已被证明在调节内皮细胞存活和周细胞募集中起关键作用，而Ang-2已被确定为一种血管不稳定因子，在控制血管生成或血管退化中起主要作用。最近的研究表明，在动物模型和糖尿病患者中，Ang-2都异常升高。此外，高血糖诱导的ang2有助于糖尿病视网膜血管周细胞的损失。迄今为止，关于高血糖诱导的ang2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，并阻断ang -1诱导的心肌内皮细胞迁移，这表明Ang-2的异常对糖尿病心肌血管生成有不利影响。在此之前，我们观察到Ang-1通过上调猪冠状动脉内皮细胞的热休克蛋白90 (Hsp90)/eNOS相互作用来刺激血管生成。因此，我们提出，高血糖诱导的ang2破坏了ang1 /Hsp90客户蛋白的相互作用，并有助于心肌内皮不稳定和心肌血管生成的损害。为了探索我们的观点，我们将使用db/db糖尿病小鼠模型，研究是否：(1)高血糖诱导的ang2破坏ang1介导的Hsp90/client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障碍；(2)通过促进Hsp90/client蛋白相互作用和周细胞募集，Ang-1预处理可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诱导的血管生成障碍的重要新机制，并为开发治疗糖尿病血管生成异常的新治疗策略提供框架。

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.