Deciphering cell-specific effects of homoarginine in atherosclerosis

• Applicant: Dorothee Atzler, Ph.D.
• Subject Area: Pharmacology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549125635

Homoarginine (HA) is an endogenous amino acid, structurally related to L-arginine. During the past decade, epidemiological and clinical studies established low circulating HA as a strong biomarker for cardiovascular (CV) outcome and mortality. Using mouse models, I showed a causal link between HA-supplementation and improved CV outcome. However, while various hypotheses had been postulated, the underlying mechanisms of HA remain elusive. Recently, I found that HA-supplementation inhibits atherosclerosis via inhibition of myosin IIA in T cells, a pivotal cell type in atherosclerosis. These results were ground-breaking, as they provide a proof-of-principle as well as a first mechanistic explanation for beneficial effects of HA in vascular disease. CV disease (CVD) with atherosclerosis as major underlying pathology is the leading cause of morbidity and mortality worldwide and its prevalence is still on the rise. The use of lipid-lowering therapies forms the basis of current CVD management. However, the residual inflammatory risk remains a major concern and warrants additional therapeutic strategies. This project aims at 1) clarifying HA’s physiological role, 2) why low HA is such a strong predictor and 3) HA’s cell-specific mode of action in the pathogenesis of atherosclerosis. I will use isotopic HA+11–tracing in HA-deficient and wild-type mice for spatial metabolomic and high-resolution immunohistochemistry analyses to determine the systemic and cellular distribution of supplemented and endogenous HA. Detailed mechanistic, functional and topographic analyses will disentangle cell-specific functions of HA, both under physiological conditions and in atherosclerosis. The long-term goal of this project is to identify HA’s physiological role and function in CVD in order to close the translational gaps to move HA from a biomarker towards therapy.

• DFG Programme: Research Grants