Dysregulated oxalate metabolism is a driver and therapeutic target in atherosclerosis.

Autor:	Liu Y; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha 410000, China., Zhao Y; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA., Shukha Y; Department of Internal Medicine E, Rambam Health Care Campus, Haifa 3109601, Israel; The Lipid Research Laboratory, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525433, Israel., Lu H; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA., Wang L; College of Pharmacy, Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA., Liu Z; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA., Liu C; College of Pharmacy, Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA., Zhao Y; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA., Wang H; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA., Zhao G; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA., Liang W; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA., Fan Y; Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA., Chang L; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA., Yurdagul A Jr; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA., Pattillo CB; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA., Orr AW; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA., Aviram M; The Lipid Research Laboratory, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525433, Israel., Wen B; College of Pharmacy, Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA., Garcia-Barrio MT; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA., Zhang J; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA., Liu W; Department of Pharmaceutical Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48201, USA., Sun D; College of Pharmacy, Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA., Hayek T; Department of Internal Medicine E, Rambam Health Care Campus, Haifa 3109601, Israel; The Lipid Research Laboratory, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525433, Israel., Chen YE; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: echenum@umich.edu., Rom O; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA. Electronic address: oren.rom@lsuhs.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2021 Jul 27; Vol. 36 (4), pp. 109420.
DOI:	10.1016/j.celrep.2021.109420
Abstrakt:	Dysregulated glycine metabolism is emerging as a common denominator in cardiometabolic diseases, but its contribution to atherosclerosis remains unclear. In this study, we demonstrate impaired glycine-oxalate metabolism through alanine-glyoxylate aminotransferase (AGXT) in atherosclerosis. As found in patients with atherosclerosis, the glycine/oxalate ratio is decreased in atherosclerotic mice concomitant with suppression of AGXT. Agxt deletion in apolipoprotein E-deficient (Apoe -/- ) mice decreases the glycine/oxalate ratio and increases atherosclerosis with induction of hepatic pro-atherogenic pathways, predominantly cytokine/chemokine signaling and dysregulated redox homeostasis. Consistently, circulating and aortic C-C motif chemokine ligand 5 (CCL5) and superoxide in lesional macrophages are increased. Similar findings are observed following dietary oxalate overload in Apoe -/- mice. In macrophages, oxalate induces mitochondrial dysfunction and superoxide accumulation, leading to increased CCL5. Conversely, AGXT overexpression in Apoe -/- mice increases the glycine/oxalate ratio and decreases aortic superoxide, CCL5, and atherosclerosis. Our findings uncover dysregulated oxalate metabolism via suppressed AGXT as a driver and therapeutic target in atherosclerosis. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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