Characterization of mechanisms through which coagulation proteases differentially regulate hyperglycemia and hyperlipidemia induced accelerated atherosclerosis.

凝血蛋白酶差异调节高血糖和高脂血症诱导加速动脉粥样硬化的机制的表征。

基本信息

批准号：
61478778
负责人：
Professor Dr. Berend Isermann
金额：
--
依托单位：
Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/61478778?language=en
关键词：
Characterization mechanisms through coagulation proteases

项目摘要

The role of coagulation proteases, in particular protease dependent signalling, for the establishment of atherosclerosis is unknown. Thrombin and activated protein C (PC) are two key regulators of the coagulation system with opposing effects in regard to coagulation activation. They provoke differential intracellular signalling despite activation of the same receptor, protease activated receptor 1 (PAR-1). Activity of thrombin and activated PC is determined by the thrombin binding endothelial protein thrombomodulin (TM), which inhibits thrombin and activates PC. Thus, TM has a key role in determining activity of thrombin, activated PC and secondary effects mediated through these proteases. Expression of receptors for coagulation proteases (PAR´s, TM, EPCR (endothelial protein C receptor)) has been established in cell-types relevant for cardiovascular disease. However, the mechanisms through which TM, thrombin and activated PC evoke differential intracellular signalling and the relation to chronic cardiovascular disease are not understood. We have been able to show that TM modulates atherosclerosis and cardiac hypertrophy in vivo. In vitro results suggest that TM might modulate cellular function (e.g. NF-kB activation, expression of adhesion molecules) through two mechanisms: (A) inhibition of thrombin dependent cell activation and (B) promotion of activated PC dependent cytoprotection. The aim of the proposal is to identify the mechanism through which TM modulates differential cell activation and cardiovascular disease. Using in vivo and in vitro experiments we intend to: 1) Identify the mechanism through which thrombin and activated PC differentially regulate NF-kB activation and expression of adhesion molecules; 2) Determining whether TM has direct signalling properties; 3) Define the role of TM-dependent regulation of thrombin and activated PC for atherosclerosis in vivo; 4) Determine whether the TM-PC system regulates cardiac hypertrophy indirectly (via regulation of arterial blood pressure) or directly through receptor dependent mechanisms. The current proposal will provide an in depth analysis of the mechanisms through which thrombin, activated PC, and TM regulate cardiovascular disease. Animal models of accelerated atherosclerosis (high fat diet or hyperglycemia) and with genetically altered activity of the TM-PC system will be used. These in vivo experiments will be paired with complementary in vitro studies. The long term aim of the proposed studies is an in depth understanding of the mechanisms through which the coagulation system regulates cardiovascular disease. This work will lay ground for novel targeted therapeutic intervention based on the mechanisms regulated by coagulation proteases, but circumventing associated problems such as increased risk of hemorrhage.

凝血蛋白酶C蛋白C（PC）的作用是凝血系统的两个关键调节剂，尽管蛋白酶激活了蛋白酶激活的受体1。因此，抑制TM在确定通过这些蛋白酶介导的螺栓效应（PAR，TM，EPCR（荷兰蛋白质C接收器））具有关键的Rolee通过TM，凝血酶和激活的PC引起的细胞内信号传导以及与慢性心血管se骨的关系不了解，我们已经调节了动脉粥样硬化和心脏肥大。两种机制：（a）抑制血栓细胞离子和（b）促进活化的PC依赖性细胞保护作用。粘附分子的激活和表达； 3）ect信号传导特性；在体内定义凝血酶和激活的PC的作用MS对凝血酶饮食或高血糖的动物模型（高脂肪饮食或高血糖）以及TM-PC系统的遗传变化，对凝血酶的动物模型进行了深入分析长期的体外研究研究是基于常规蛋白酶的凝血系统心脏凝血系统的凝结系统。