TY - JOUR
T1 - The Amino Acid Homoarginine Inhibits Atherogenesis by Modulating T-Cell Function
AU - Nitz, Katrin
AU - Lacy, Michael
AU - Bianchini, Mariaelvy
AU - Wichapong, Kanin
AU - Kücükgöze, Irem Avcilar
AU - Bonfiglio, Cecilia A.
AU - Migheli, Roberta
AU - Wu, Yuting
AU - Burger, Carina
AU - Li, Yuanfang
AU - Forné, Ignasi
AU - Ammar, Constantin
AU - Janjic, Aleksandar
AU - Mohanta, Sarajo
AU - Duchene, Johan
AU - Heemskerk, Johan W.M.
AU - Megens, Remco T.A.
AU - Schwedhelm, Edzard
AU - Huveneers, Stephan
AU - Lygate, Craig A.
AU - Santovito, Donato
AU - Zimmer, Ralf
AU - Imhof, Axel
AU - Weber, Christian
AU - Lutgens, Esther
AU - Atzler, Dorothee
N1 - Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.
PY - 2022/9/30
Y1 - 2022/9/30
N2 - Background: Amino acid metabolism is crucial for inflammatory processes during atherogenesis. The endogenous amino acid homoarginine is a robust biomarker for cardiovascular outcome and mortality with high levels being protective. However, the underlying mechanisms remain elusive. We investigated the effect of homoarginine supplementation on atherosclerotic plaque development with a particular focus on inflammation. Methods: Female ApoE-deficient mice were supplemented with homoarginine (14 mg/L) in drinking water starting 2 weeks before and continuing throughout a 6-week period of Western-type diet feeding. Control mice received normal drinking water. Immunohistochemistry and flow cytometry were used for plaque- and immunological phenotyping. T cells were characterized using mass spectrometry-based proteomics, by functional in vitro approaches, for example, proliferation and migration/chemotaxis assays as well as by super-resolution microscopy. Results: Homoarginine supplementation led to a 2-fold increase in circulating homoarginine concentrations. Homoarginine-treated mice exhibited reduced atherosclerosis in the aortic root and brachiocephalic trunk. A substantial decrease in CD3+T cells in the atherosclerotic lesions suggested a T-cell-related effect of homoarginine supplementation, which was mainly attributed to CD4+T cells. Macrophages, dendritic cells, and B cells were not affected. CD4+T-cell proteomics and subsequent pathway analysis together with in vitro studies demonstrated that homoarginine profoundly modulated the spatial organization of the T-cell actin cytoskeleton and increased filopodia formation via inhibition of Myh9 (myosin heavy chain 9). Further mechanistic studies revealed an inhibition of T-cell proliferation as well as a striking impairment of the migratory capacities of T cells in response to relevant chemokines by homoarginine, all of which likely contribute to its atheroprotective effects. Conclusions: Our study unravels a novel mechanism by which the amino acid homoarginine reduces atherosclerosis, establishing that homoarginine modulates the T-cell cytoskeleton and thereby mitigates T-cell functions important during atherogenesis. These findings provide a molecular explanation for the beneficial effects of homoarginine in atherosclerotic cardiovascular disease.
AB - Background: Amino acid metabolism is crucial for inflammatory processes during atherogenesis. The endogenous amino acid homoarginine is a robust biomarker for cardiovascular outcome and mortality with high levels being protective. However, the underlying mechanisms remain elusive. We investigated the effect of homoarginine supplementation on atherosclerotic plaque development with a particular focus on inflammation. Methods: Female ApoE-deficient mice were supplemented with homoarginine (14 mg/L) in drinking water starting 2 weeks before and continuing throughout a 6-week period of Western-type diet feeding. Control mice received normal drinking water. Immunohistochemistry and flow cytometry were used for plaque- and immunological phenotyping. T cells were characterized using mass spectrometry-based proteomics, by functional in vitro approaches, for example, proliferation and migration/chemotaxis assays as well as by super-resolution microscopy. Results: Homoarginine supplementation led to a 2-fold increase in circulating homoarginine concentrations. Homoarginine-treated mice exhibited reduced atherosclerosis in the aortic root and brachiocephalic trunk. A substantial decrease in CD3+T cells in the atherosclerotic lesions suggested a T-cell-related effect of homoarginine supplementation, which was mainly attributed to CD4+T cells. Macrophages, dendritic cells, and B cells were not affected. CD4+T-cell proteomics and subsequent pathway analysis together with in vitro studies demonstrated that homoarginine profoundly modulated the spatial organization of the T-cell actin cytoskeleton and increased filopodia formation via inhibition of Myh9 (myosin heavy chain 9). Further mechanistic studies revealed an inhibition of T-cell proliferation as well as a striking impairment of the migratory capacities of T cells in response to relevant chemokines by homoarginine, all of which likely contribute to its atheroprotective effects. Conclusions: Our study unravels a novel mechanism by which the amino acid homoarginine reduces atherosclerosis, establishing that homoarginine modulates the T-cell cytoskeleton and thereby mitigates T-cell functions important during atherogenesis. These findings provide a molecular explanation for the beneficial effects of homoarginine in atherosclerotic cardiovascular disease.
KW - amino acid
KW - atherosclerosis
KW - biomarker
KW - cardiovascular disease
KW - homoarginine
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U2 - 10.1161/CIRCRESAHA.122.321094
DO - 10.1161/CIRCRESAHA.122.321094
M3 - Article
C2 - 36102188
AN - SCOPUS:85139379793
SN - 0009-7330
VL - 131
SP - 701
EP - 712
JO - Circulation research
JF - Circulation research
IS - 8
ER -