The role of arginine/arginase 1 metabolism in atherosclerosis

• Applicant: Dorothee Atzler, Ph.D.
• Subject Area: Pharmacology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 451372580

Cardiovascular disease is the leading cause of death worldwide with atherosclerosis representing the major underlying pathology. Although atherosclerosis is widely accepted as a chronic inflammatory condition, current therapies only focus on lipid-lowering rather than targeting the inflammatory response. Recently, intracellular metabolic pathways have been identified as master switches of immune cell function and thus seem promising targets for therapeutic interventions aimed at lowering inflammation and thereby ameliorating atherogenesis. Within athero-inflammation, immune cells use several metabolic traits to meet cellular demands in response to their inflammatory microenvironment, with amino acids, arginine, glutamine, and tryptophan constituting an important energy source. Decades of research have clearly demonstrated the importance of the amino acid L-arginine (Arg) in cardiovascular disease. However, so far most research has focused on endothelium-dependent effects of Arg, although Arg metabolism - mainly through its metabolizing enzyme arginase 1 (ARG1) - has also been shown to regulate immune cell responses, independent of its endothelial functions. The purpose of this proposal is to thoroughly investigate the ARG1 pathway in atherosclerosis. Specifically, we aim at unraveling the cell-specific role of ARG1 on atherosclerotic plaque development. We will first map and compare ARG1-dependent metabolism under baseline and atherosclerotic conditions. Second, we will use precise cell-specific models, starting with endothelial (VE-cadherin) and monocytes/macrophages–specific (CX3CR1) ARG1 knockout mice to elucidate cell-specific effects on atherosclerosis in vivo. We hypothesize that Arg/ARG1 metabolism is strongly upregulated during atherogenesis. Further, we hypothesize, that endothelial-specific ARG1 deficiency exerts protective effects, while depletion in monocytes and macrophages aggravates atherosclerotic plaque burden, potentially through modulations of intracellular metabolic processes in monocytes, macrophages and surrounding T cells.We will specifically address the following points:1. Which cells/cell subsets use the Arg/ARG1 pathway at steady state? And how is this pathway regulated during atherogenesis? 2. Do endothelial and/or monocytes/macrophages-directed ARG1 deficiencies alter atherosclerotic plaque development?3. How does the Arg/ARG1 metabolism control immune cell and endothelial function in atherosclerosis?The overall purpose of this project is to focus on the cell-specific Arg/ARG1 metabolism in immune and endothelial cells to identify its potential as a therapeutic target for the treatment of atherosclerosis.

• DFG Programme: Research Grants