The Amino Acid Homoarginine Inhibits Atherogenesis by Modulating T-Cell Function
| العنوان: | The Amino Acid Homoarginine Inhibits Atherogenesis by Modulating T-Cell Function |
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| المؤلفون: | Katrin Nitz, Michael Lacy, Mariaelvy Bianchini, Kanin Wichapong, Irem Avcilar Kücükgöze, Cecilia A. Bonfiglio, Roberta Migheli, Yuting Wu, Carina Burger, Yuanfang Li, Ignasi Forné, Constantin Ammar, Aleksandar Janjic, Sarajo Mohanta, Johan Duchene, Johan W.M. Heemskerk, Remco T.A. Megens, Edzard Schwedhelm, Stephan Huveneers, Craig A. Lygate, Donato Santovito, Ralf Zimmer, Axel Imhof, Christian Weber, Esther Lutgens, Dorothee Atzler |
| المساهمون: | Medical Biochemistry, ACS - Atherosclerosis & ischemic syndromes, ACS - Microcirculation, AII - Inflammatory diseases, Biochemie, RS: Carim - B01 Blood proteins & engineering, RS: Carim - B03 Cell biochemistry of thrombosis and haemostasis, Biomedische Technologie |
| المصدر: | Circulation research, 131(8), 701-712. Lippincott Williams and Wilkins Circulation Research, 131(8), 701-712. LIPPINCOTT WILLIAMS & WILKINS |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Myosin Heavy Chains, Physiology, Drinking Water, T-Lymphocytes, Plaque, Atherosclerotic, Mice, Apolipoproteins E, cardiovascular disease, Animals, biomarker, homoarginine, Female, Amino Acids, atherosclerosis, Cardiology and Cardiovascular Medicine, amino acid |
| الوصف: | 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. |
| تدمد: | 1524-4571 0009-7330 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::642fc6b87cae0b8a00e5cf36ec8664f0Test https://doi.org/10.1161/circresaha.122.321094Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....642fc6b87cae0b8a00e5cf36ec8664f0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244571 00097330 |
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