Kallistatin in Vascular Injury

描述（由申请人提供）：本提案的目的是确定卡利司他汀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生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，通过为受损和衰老血管提供持续的补充来源，修复EPC数量和功能是一种很有前景的内皮修复方法。卡利司他汀，一种血浆蛋白，是在我们实验室发现的。我们已经在动物模型和培养细胞中证明了卡利司他汀通过抑制炎症和氧化应激对心血管和肾功能障碍具有多重保护作用。重要的是，卡利司他汀增加高血压大鼠循环EPC水平，降低主动脉氧化应激，促进培养EPCs的迁移和延缓衰老。我们的中心假设是，卡利司他汀通过刺激EPC动员和功能活动来防止血管损伤，并通过减少氧化应激和增强一氧化氮的产生来减少EPC衰老。我们将追求以下具体目标：1)确定kallistatin通过增强EPC迁移、粘附、管形成和增殖来促进血管修复的机制；2)确定卡利司他汀通过抑制内皮细胞内皮细胞衰老来预防血管损伤的机制；3)在高血压大鼠、转基因小鼠和基因敲除小鼠中，通过给药和减药的方法来确定卡利司他汀在内皮损伤中的新作用。该研究的结果有望通过提供一种基于卡司他汀的新方法来改善血管疾病的内皮修复，从而产生重要的积极影响。

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.