Induction of glutathione biosynthesis by glycine-based treatment mitigates atherosclerosis
Oren Rom,
Yuhao Liu,
Alexandra C. Finney,
Alia Ghrayeb,
Ying Zhao,
Yousef Shukha,
Lu Wang,
Krishani K. Rajanayake,
Sandeep Das,
Nabil A. Rashdan,
Natan Weissman,
Luisa Delgadillo,
Bo Wen,
Minerva T. Garcia-Barrio,
Michael Aviram,
Christopher G. Kevil,
Arif Yurdagul, Jr.,
Christopher B. Pattillo,
Jifeng Zhang,
Duxin Sun,
Tony Hayek,
Eyal Gottlieb,
Inbal Mor,
Y Eugene Chen
Affiliations
Oren Rom
Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA; Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA; Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA; Corresponding author. Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Highway, Shreveport, LA, 71103, USA.
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
Alexandra C. Finney
Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA
Alia Ghrayeb
The Laboratory for Metabolism in Health and Disease, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel
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, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 3525433, Israel
Lu Wang
College of Pharmacy, Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA
Krishani K. Rajanayake
College of Pharmacy, Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, 48109, USA
Sandeep Das
Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA
Nabil A. Rashdan
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA
Natan Weissman
The Laboratory for Metabolism in Health and Disease, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel
Luisa Delgadillo
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA
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
Michael Aviram
The Lipid Research Laboratory, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 3525433, Israel
Christopher G. Kevil
Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA; Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA; Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA
Arif Yurdagul, Jr.
Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA
Christopher B. Pattillo
Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA
Jifeng Zhang
Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, 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, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 3525433, Israel
Eyal Gottlieb
The Laboratory for Metabolism in Health and Disease, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel
Inbal Mor
The Laboratory for Metabolism in Health and Disease, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, Israel
Y Eugene Chen
Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI, 48109, USA; Corresponding author. Department of Internal Medicine, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA.
Lower circulating levels of glycine are consistently reported in association with cardiovascular disease (CVD), but the causative role and therapeutic potential of glycine in atherosclerosis, the underlying cause of most CVDs, remain to be established. Here, following the identification of reduced circulating glycine in patients with significant coronary artery disease (sCAD), we investigated a causative role of glycine in atherosclerosis by modulating glycine availability in atheroprone mice. We further evaluated the atheroprotective potential of DT-109, a recently identified glycine-based compound with dual lipid/glucose-lowering properties. Glycine deficiency enhanced, while glycine supplementation attenuated, atherosclerosis development in apolipoprotein E-deficient (Apoe−/−) mice. DT-109 treatment showed the most significant atheroprotective effects and lowered atherosclerosis in the whole aortic tree and aortic sinus concomitant with reduced superoxide. In Apoe−/− mice with established atherosclerosis, DT-109 treatment significantly reduced atherosclerosis and aortic superoxide independent of lipid-lowering effects. Targeted metabolomics and kinetics studies revealed that DT-109 induces glutathione formation in mononuclear cells. In bone marrow-derived macrophages (BMDMs), glycine and DT-109 attenuated superoxide formation induced by glycine deficiency. This was abolished in BMDMs from glutamate-cysteine ligase modifier subunit-deficient (Gclm−/-) mice in which glutathione biosynthesis is impaired. Metabolic flux and carbon tracing experiments revealed that glycine deficiency inhibits glutathione formation in BMDMs while glycine-based treatment induces de novo glutathione biosynthesis. Through a combination of studies in patients with CAD, in vivo studies using atherosclerotic mice and in vitro studies using macrophages, we demonstrated a causative role of glycine in atherosclerosis and identified glycine-based treatment as an approach to mitigate atherosclerosis through antioxidant effects mediated by induction of glutathione biosynthesis.
