Importance of erythrocyte arginase-1 for vascular homeostasis and disease

• Applicant: Professorin Dr. Katrin Schäfer
• Subject Area: Cardiology, Angiology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 329795682

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.

• DFG Programme: Research Grants