Kallistatin in Vascular Injury

本提案的目的是确定激肽释放酶抑制剂在以下方面的作用和机制： 修复血管损伤内皮细胞损伤在血管内皮细胞损伤的发生发展中起着关键作用。 血管疾病已经表明，内皮细胞的数量和迁移能力， 在心血管疾病患者中，祖细胞（EPCs）减少。因此，我们认为， EPC数量和功能的恢复是一种有前途的内皮修复方法， 为受损和衰老的血管提供持续的补充来源。 Kallistatin是一种血浆蛋白，是在我们实验室发现的。我们已经证明 激肽释放酶抑制剂对心血管和肾功能障碍发挥多种保护作用， 在动物模型和培养细胞中抑制炎症和氧化应激。重要的是， 激肽释放酶抑制剂增加循环内皮祖细胞水平并降低主动脉氧化应激， 高血压大鼠，以及促进迁移和减少衰老， 培养的EPCs我们的中心假设是，激肽释放酶抑制剂通过以下方式防止血管损伤： 刺激EPC动员和功能活性，并通过以下途径减少EPC衰老： 减少氧化应激和增强一氧化氮的产生。我们将继续 以下具体目的：1）确定激肽释放酶抑制剂促进血管生成的机制， 通过增强EPC迁移、粘附、管形成和增殖来修复; 2）确定 激肽抑制素通过抑制内皮祖细胞衰老预防血管损伤的机制; 3）通过使用Kalistatin确定Kalistatin在内皮损伤中的新作用 高血压大鼠的给药和激肽释放酶抑制剂耗竭方法， 转基因小鼠和敲除小鼠。预期拟议研究的成果 通过提供一种使用基于激肽的新方法， 改善血管疾病的内皮修复的治疗。

The objective of this proposal is to determine the role and mechanisms of kallistatin in repairing vascular injury. Endothelial damage plays a pivotal role in the development of vascular diseases. It has been shown that the number and migratory capacity of endothelial progenitor cells (EPCs) are decreased in patients with cardiovascular diseases. Therefore, restoration of EPC number and function is a promising approach to endothelial repair by providing a continuous source of replenishment for damaged and senescent vessels. Kallistatin, a plasma protein, was discovered in our laboratory. We have demonstrated that kallistatin exerts multiple protective effects against cardiovascular and renal dysfunction by inhibiting inflammation and oxidative stress in animal models and cultured cells. Importantly, kallistatin increases circulating EPC levels and reduces aortic oxidative stress in hypertensive rats, as well as promotes the migration and decreases the senescence of cultured EPCs. Our central hypothesis is that kallistatin prevents vascular damage by stimulating EPC mobilization and functional activity and reducing EPC senescence through decreased oxidative stress and enhanced nitric oxide production. We will pursue the following specific aims: 1) determine the mechanisms by which kallistatin promotes vascular repair by enhancing EPC migration, adhesion, tube formation and proliferation; 2) determine the mechanisms by which kallistatin prevents vascular injury by inhibiting EPC senescence; and 3) determine the novel role of kallistatin in endothelial injury by using kallistatin administration and kallistatin depletion approaches in hypertensive rats, kallistatin transgenic mice and knockout mice. The outcomes of the proposed research are expected to have an important positive impact by providing a novel approach using kallistatin-based therapy to improve endothelial repair for vascular diseases.