Kallistatin in Vascular Injury

描述(由申请人提供)：本提案的目的是确定kalistatin在修复血管损伤中的作用和机制。血管内皮细胞损伤在血管疾病的发展中起着关键作用。已有研究表明，心血管疾病患者内皮祖细胞数量减少，迁移能力降低。因此，通过为受损和衰老的血管提供持续的补充来源，恢复内皮祖细胞的数量和功能是一种很有前途的内皮修复方法。卡利斯汀是我们实验室发现的一种血浆蛋白。我们已经证明，Kalistatin通过抑制动物模型和培养细胞中的炎症和氧化应激，对心血管和肾功能障碍具有多种保护作用。重要的是，Kalistatin可增加高血压大鼠循环内皮祖细胞的水平，减少主动脉氧化应激，并促进培养的内皮祖细胞迁移和减少衰老。我们的中心假设是，Kalistatin通过刺激EPC动员和功能活性来防止血管损伤，并通过减少氧化应激和增加一氧化氮的产生来减缓EPC的衰老。我们将追求以下具体目标：1)确定kallistatin通过促进内皮祖细胞迁移、黏附、管子形成和增殖促进血管修复的机制；2)确定kallistatin通过抑制EPC衰老来防止血管损伤的机制；以及3)通过在高血压大鼠、kallistatin转基因小鼠和基因敲除小鼠中使用kallistatin给药和kallistatin耗竭途径，确定kallistatin在内皮损伤中的新作用。这项拟议研究的结果有望产生重要的积极影响，因为它提供了一种新的方法，使用基于kallistatin的疗法来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.