Kallistatin in Hypertension

描述（由申请人提供）：本申请的目的是研究卡利司他汀对高血压和缺血性心脏病引起的心脏损伤的保护作用。卡利司他汀是我们实验室发现、纯化和克隆的一种特殊的组织卡利司他汀结合蛋白和一种独特的丝氨酸蛋白酶抑制剂。纯化的卡利司他汀是一种有效的新型血管扩张剂，因为它直接诱导血管松弛并降低血压，而不依赖于它的抑制活性。过表达卡利司他汀的转基因小鼠具有低血压作用，在高血压大鼠中传递卡利司他汀基因可使血压持续降低。此外，在与炎症和氧化应激增加相关的高血压、心脏和肾脏功能障碍动物模型中，循环卡利司他汀水平显著降低。这些发现提示卡利司他汀在炎症相关性高血压和心血管疾病中的潜在作用。

DESCRIPTION (provided by applicant): The objective of this application is to investigate the role of kallistatin in protection against cardiac injury induced by hypertension and ischemic heart disease. Kallistatin was discovered, purified and cloned in our laboratory as a specific tissue kallikrein-binding protein and a unique serine proteinase inhibitor. Purified kallistatin is a potent new vasodilator as it directly induces vasorelaxation and reduces blood pressure independent of its kallikrein inhibitory activity. Transgenic mice overexpressing kallistatin are hypotensive, and kallistatin gene delivery in hypertensive rats causes a prolonged reduction of blood pressure. Furthermore, circulating kallistatin levels are markedly reduced in animal models of hypertension, cardiac and renal dysfunction associated with increased inflammation and oxidative stress. These findings suggest a potential role of kallistatin in inflammation-related hypertension and cardiovascular disease. Our recent studies showed that kallistatin gene transfer reduced inflammatory cytokines and joint swelling in collagen-induced arthritis, and reduced inflammatory cell infiltration and apoptosis in the ischemic heart after ischemia/reperfusion (I/R). Based on these new findings, we hypothesize that kallistatin protects against hypertension and ischemic heart disease by inhibiting oxidative stress, inflammation and cardiomyocyte apoptosis. In order to test this hypothesis, we will pursue the following specific aims: 1) to determine the structural elements of kallistatin required for inhibiting inflammation and cardiomyocyte apoptosis after myocardial I/R, 2) to determine the signaling pathways mediated by kallistatin in inhibiting inflammation after myocardial I/R, 3) to determine the signaling pathways mediated by kallistatin in inhibiting apoptosis after myocardial I/R, and 4) to determine the protective role of endogenous kallistatin in hypertension and ischemic heart disease using kallistatin knockout mice and kallistatin knockdown rats by RNA interference. This research proposal should provide significant insights into the role and regulatory mechanisms of kallistatin in the cardiovascular system, and foster the development of therapeutic agents for halting inflammation-related hypertension and ischemic heart disease.