Cell Reports (Jul 2021)
Dysregulated oxalate metabolism is a driver and therapeutic target in atherosclerosis
- Yuhao Liu,
- Ying Zhao,
- Yousef Shukha,
- Haocheng Lu,
- Lu Wang,
- Zhipeng Liu,
- Cai Liu,
- Yang Zhao,
- Huilun Wang,
- Guizhen Zhao,
- Wenying Liang,
- Yanbo Fan,
- Lin Chang,
- Arif Yurdagul, Jr.,
- Christopher B. Pattillo,
- A. Wayne Orr,
- Michael Aviram,
- Bo Wen,
- Minerva T. Garcia-Barrio,
- Jifeng Zhang,
- Wanqing Liu,
- Duxin Sun,
- Tony Hayek,
- Y. Eugene Chen,
- Oren Rom
Affiliations
- Yuhao Liu
- 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
- Ying Zhao
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA
- Yousef Shukha
- 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
- Haocheng Lu
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA
- Lu Wang
- College of Pharmacy, Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA
- Zhipeng Liu
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
- Cai Liu
- College of Pharmacy, Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA
- Yang Zhao
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA
- Huilun Wang
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA
- Guizhen Zhao
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA
- Wenying Liang
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA
- Yanbo Fan
- Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
- Lin Chang
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA
- Arif Yurdagul, Jr.
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA
- Christopher B. Pattillo
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA
- A. Wayne Orr
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA 71103, USA
- Michael Aviram
- The Lipid Research Laboratory, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525433, Israel
- Bo Wen
- College of Pharmacy, Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA
- Minerva T. Garcia-Barrio
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA
- Jifeng Zhang
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA
- Wanqing Liu
- Department of Pharmaceutical Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48201, USA
- Duxin Sun
- College of Pharmacy, Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA
- Tony Hayek
- 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
- Y. Eugene Chen
- Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding author
- Oren Rom
- 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; Corresponding author
- Journal volume & issue
-
Vol. 36,
no. 4
p. 109420
Abstract
Summary: 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.
