Kallistatin in Vascular Injury

描述（由申请人提供）：本提案的目的是确定激肽在修复血管损伤中的作用和机制。内皮损伤在血管疾病的发展中起着关键作用。研究表明，心血管疾病患者内皮祖细胞（EPCs）的数量和迁移能力下降。因此，通过为受损和衰老的血管提供持续的补充来源，恢复EPC数量和功能是一种有前途的内皮修复方法。Kallistatin是一种血浆蛋白，是在我们实验室发现的。我们已经证明，在动物模型和培养细胞中，激肽释放酶抑制剂通过抑制炎症和氧化应激对心血管和肾功能障碍发挥多种保护作用。更重要的是，激肽释放酶抑制剂增加循环EPC水平，降低高血压大鼠主动脉氧化应激，以及促进迁移和减少培养的EPCs的衰老。我们的中心假设是，激肽通过刺激EPC动员和功能活性，并通过减少氧化应激和增强一氧化氮的产生减少EPC衰老，从而预防血管损伤。本研究的主要目的是：1）明确Kallistatin通过促进EPC迁移、粘附、管腔形成和增殖促进血管修复的机制; 2）明确Kallistatin通过抑制EPC衰老预防血管损伤的机制;和3）通过在高血压大鼠中使用Kalistatin给药和Kalistatin耗竭方法来确定Kalistatin在内皮损伤中的新作用，激肽释放酶抑制剂转基因小鼠和敲除小鼠。拟议研究的结果预计将产生重要的积极影响，提供一种新的方法，使用基于激肽的治疗，以改善血管疾病的内皮修复。

DESCRIPTION (provided by applicant): 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 depleion 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.