Importance of erythrocyte arginase-1 for vascular homeostasis and disease

红细胞精氨酸酶 1 对血管稳态和疾病的重要性

• 批准号: 329795682
• 负责人: Professorin Dr. Katrin Schäfer
• 金额: --
• 依托单位: Kardiologie I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/329795682?language=en
• 关键词: Importance; erythrocyte; arginase; vascular; homeostasis

Experimental evidence and first clinical data suggest that erythrocytes actively participate in vascular function control. However, the concept that erythrocytes directly act on cells of the vessel wall and contribute in cardiovascular disease processes has only recently emerged, and the mediators and signalling pathways involved in their erythrocrine activities are largely unknown. During the first funding period of this project we have shown that nitric oxide from lysed erythrocyte membranes promotes smooth muscle cell mineralisation and atherosclerotic lesion calcification. Based on these findings, we generated hypercholesterolaemic mice lacking arginase-1 specifically in red blood cells to shift the arginase-eNOS balance in erythrocytes towards increased NO generation. The ongoing characterisation of this new mouse line could confirm that the enhanced release of NO from erythrocytes promotes vascular calcification in vitro and in vivo. In addition, we observed that the increased NO bioavailability has systemic effects on vascular homeostasis suggesting a major role of erythrocytes in these processes. In the second funding period, we therefore plan to examine the contribution of erythrocytes to vascular homeostasis and disease processes in more detail. Specifically, we will phenotype mice with erythrocyte-specific arginase-1 deletion and increased erythrocyte-derived NO release, both on the C57BL6/J and the hypercholesterolaemic apolipoprotein E-deficient background, including vascular function regulation (WP1), neointima formation (WP2) and atherosclerotic plaque progression and stability (WP3). To determine the contribution of red blood cell arginase-1 to systemic NO bioavailability, findings will be compared to mice with endothelial cell-specific arginase deletion. Based on observations that NO may act via inducing the synthesis of other gasotransmitters in vascular cells and own preliminary data, we will examine the response of endothelial and smooth muscle cells after pharmacological inhibition or RNAi-mediated genetic loss-of-function of H2S generating enzymes to murine and human erythrocytes. To translate our findings in mice and cells to humans, differences in the expression and activity of factors involved in the bioavailability of NO and signal transduction in the vascular system will be examined in RBCs from patients at risk or with established cardiovascular disease.

实验证据和初步临床数据表明，红细胞积极参与血管功能控制。然而，红细胞直接作用于血管壁细胞并参与心血管疾病过程的概念直到最近才出现，并且参与其红细胞活动的介质和信号通路在很大程度上是未知的。在这个项目的第一个资助期，我们已经表明，从溶解的红细胞膜一氧化氮促进平滑肌细胞矿化和动脉粥样硬化病变钙化。基于这些发现，我们制造了高胆固醇血症小鼠，在红细胞中特异性缺乏精氨酸酶-1，以改变红细胞中精氨酸酶- enos平衡，增加NO的产生。对这一新小鼠品系的持续表征可以证实，红细胞中一氧化氮释放的增强促进了体外和体内血管钙化。此外，我们观察到一氧化氮生物利用度的增加对血管稳态有全身影响，表明红细胞在这些过程中起主要作用。因此，在第二个资助期，我们计划更详细地研究红细胞对血管稳态和疾病过程的贡献。具体来说，我们将在C57BL6/J和高胆固醇血症载脂蛋白e缺乏背景下，对红细胞特异性精氨酸酶-1缺失和红细胞源性NO释放增加的小鼠进行表型分析，包括血管功能调节（WP1）、新内膜形成（WP2）和动脉粥样硬化斑块进展和稳定性（WP3）。为了确定红细胞精氨酸酶-1对全身NO生物利用度的贡献，研究结果将与内皮细胞特异性精氨酸酶缺失的小鼠进行比较。基于NO可能通过诱导血管细胞中其他气体递质的合成而起作用的观察和自己的初步数据，我们将研究内皮细胞和平滑肌细胞在药物抑制或rnai介导的H2S生成酶基因功能丧失后对小鼠和人红细胞的反应。为了将我们在小鼠和细胞中的发现转化为人类，我们将在危险患者或已确诊心血管疾病患者的红细胞中检查与血管系统中NO生物利用度和信号转导相关的因子的表达和活性的差异。