The amino acid homoarginine inhibits atherogenesis by modulating T-cell function

ABSTRACT: Rational: Amino acid metabolism is crucial for inflammatory processes during atherogenesis. The endogenous amino acid homoarginine (HA) is a robust biomarker for cardiovascular outcome and mortality with high levels being protective. However, the underlying molecular mechanism remains elusive. Objective: We investigated the effect of HA supplementation on atherosclerotic plaque development with a particular focus on athero-inflammation. Methods and Results: Female apolipoprotein (Apo) E-deficient mice were supplemented with HA (14 mg/L) in drinking water starting two weeks before and continuing throughout a six week-course of Western-type diet (HA-treated). Control mice (Ctrl) received normal drinking water. HA supplementation led to a 2-fold increase in circulating HA concentrations. Plaque- and immunological phenotyping revealed that HA-treated mice exhibited a reduction in atherosclerosis in the aortic root as well as in the brachiocephalic trunk. A substantial decrease in lesion CD3+ T cells suggested a T cell-related effect of HA supplementation. Using mass spectrometry-based proteomics and subsequent pathway analysis together with conventional in vitro techniques such as flow cytometry, various migration and chemotaxis assays as well as super-resolution microscopy, we demonstrate that HA profoundly modulated the spatial organization of the T-cell actin cytoskeleton. Further mechanistic studies revealed an inhibition of T-cell activation and proliferation as well as a striking impairment of the migratory capacities of T cells in response to relevant chemokines by HA, all of which likely contribute to its atheroprotective effects. Conclusion: This study unravels a novel mechanism, by which the amino acid HA reduces atherosclerosis, namely the regulation of T-cell functions crucial for adaptive immunity. We identified that HA modulates the T-cell cytoskeleton and thereby mitigated important T-cell functions during atherogenesis. These findings provide a molecular explanation for the beneficial effects of HA in atherosclerotic cardiovascular disease.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Spleen, T Cell, Lymph Node, Blood

DISEASE(S): Atherosclerosis

SUBMITTER: Ignasi Forne  

LAB HEAD: Dorothee Atzler, PhD

PROVIDER: PXD023960 | Pride | 2023-01-30

REPOSITORIES: Pride