PMID- 35447412
OWN - NLM
STAT- MEDLINE
DCOM- 20220510
LR  - 20220716
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 52
DP  - 2022 Jun
TI  - Induction of glutathione biosynthesis by glycine-based treatment mitigates 
      atherosclerosis.
PG  - 102313
LID - S2213-2317(22)00085-4 [pii]
LID - 10.1016/j.redox.2022.102313 [doi]
LID - 102313
AB  - 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.
CI  - Copyright (c) 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
FAU - Rom, Oren
AU  - Rom O
AD  - 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. Electronic address: oren.rom@lsuhs.edu.
FAU - Liu, Yuhao
AU  - Liu Y
AD  - 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.
FAU - Finney, Alexandra C
AU  - Finney AC
AD  - Department of Pathology and Translational Pathobiology, Louisiana State 
      University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA.
FAU - Ghrayeb, Alia
AU  - Ghrayeb A
AD  - The Laboratory for Metabolism in Health and Disease, Ruth and Bruce Rappaport 
      Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, 
      Israel.
FAU - Zhao, Ying
AU  - Zhao Y
AD  - Department of Internal Medicine, Frankel Cardiovascular Center, University of 
      Michigan, Ann Arbor, MI, 48109, USA.
FAU - Shukha, Yousef
AU  - Shukha Y
AD  - 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.
FAU - Wang, Lu
AU  - Wang L
AD  - College of Pharmacy, Department of Pharmaceutical Sciences, University of 
      Michigan, Ann Arbor, MI, 48109, USA.
FAU - Rajanayake, Krishani K
AU  - Rajanayake KK
AD  - College of Pharmacy, Department of Pharmaceutical Sciences, University of 
      Michigan, Ann Arbor, MI, 48109, USA.
FAU - Das, Sandeep
AU  - Das S
AD  - Department of Pathology and Translational Pathobiology, Louisiana State 
      University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA.
FAU - Rashdan, Nabil A
AU  - Rashdan NA
AD  - Department of Molecular and Cellular Physiology, Louisiana State University 
      Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA.
FAU - Weissman, Natan
AU  - Weissman N
AD  - The Laboratory for Metabolism in Health and Disease, Ruth and Bruce Rappaport 
      Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, 
      Israel.
FAU - Delgadillo, Luisa
AU  - Delgadillo L
AD  - Department of Molecular and Cellular Physiology, Louisiana State University 
      Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA.
FAU - Wen, Bo
AU  - Wen B
AD  - College of Pharmacy, Department of Pharmaceutical Sciences, University of 
      Michigan, Ann Arbor, MI, 48109, USA.
FAU - Garcia-Barrio, Minerva T
AU  - Garcia-Barrio MT
AD  - Department of Internal Medicine, Frankel Cardiovascular Center, University of 
      Michigan, Ann Arbor, MI, 48109, USA.
FAU - Aviram, Michael
AU  - Aviram M
AD  - The Lipid Research Laboratory, Ruth and Bruce Rappaport Faculty of Medicine, 
      Technion-Israel Institute of Technology, Haifa, 3525433, Israel.
FAU - Kevil, Christopher G
AU  - Kevil CG
AD  - 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.
FAU - Yurdagul, Arif Jr
AU  - Yurdagul A Jr
AD  - 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.
FAU - Pattillo, Christopher B
AU  - Pattillo CB
AD  - 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.
FAU - Zhang, Jifeng
AU  - Zhang J
AD  - Department of Internal Medicine, Frankel Cardiovascular Center, University of 
      Michigan, Ann Arbor, MI, 48109, USA.
FAU - Sun, Duxin
AU  - Sun D
AD  - College of Pharmacy, Department of Pharmaceutical Sciences, University of 
      Michigan, Ann Arbor, MI, 48109, USA.
FAU - Hayek, Tony
AU  - Hayek T
AD  - 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.
FAU - Gottlieb, Eyal
AU  - Gottlieb E
AD  - The Laboratory for Metabolism in Health and Disease, Ruth and Bruce Rappaport 
      Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, 
      Israel.
FAU - Mor, Inbal
AU  - Mor I
AD  - The Laboratory for Metabolism in Health and Disease, Ruth and Bruce Rappaport 
      Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 31096, 
      Israel.
FAU - Chen, Y Eugene
AU  - Chen YE
AD  - Department of Internal Medicine, Frankel Cardiovascular Center, University of 
      Michigan, Ann Arbor, MI, 48109, USA. Electronic address: echenum@umich.edu.
LA  - eng
GR  - R00 HL150233/HL/NHLBI NIH HHS/United States
GR  - K99 HL150233/HL/NHLBI NIH HHS/United States
GR  - R01 HL147527/HL/NHLBI NIH HHS/United States
GR  - R00 HL145131/HL/NHLBI NIH HHS/United States
GR  - P20 GM121307/GM/NIGMS NIH HHS/United States
GR  - R01 HL134569/HL/NHLBI NIH HHS/United States
GR  - R01 HL153710/HL/NHLBI NIH HHS/United States
GR  - R01 HL138139/HL/NHLBI NIH HHS/United States
GR  - R01 HL137214/HL/NHLBI NIH HHS/United States
GR  - R01 HL109946/HL/NHLBI NIH HHS/United States
GR  - R01 HL149264/HL/NHLBI NIH HHS/United States
GR  - R01 HL139755/HL/NHLBI NIH HHS/United States
GR  - U2C DK110768/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220413
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 0 (Apolipoproteins E)
RN  - 11062-77-4 (Superoxides)
RN  - EC 6.3.2.2 (Glutamate-Cysteine Ligase)
RN  - GAN16C9B8O (Glutathione)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Animals
MH  - Apolipoproteins E/genetics
MH  - *Atherosclerosis/drug therapy/genetics/metabolism
MH  - Disease Models, Animal
MH  - Glutamate-Cysteine Ligase
MH  - Glutathione/metabolism
MH  - Glycine/pharmacology/therapeutic use
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - *Plaque, Atherosclerotic/metabolism
MH  - Superoxides
PMC - PMC9044008
OTO - NOTNLM
OT  - Amino acids
OT  - Atherosclerosis
OT  - Glutathione
OT  - Glycine
OT  - Macrophages
COIS- O. Rom, Y. Zhao, J. Zhang, and Y.E. Chen have filed a patent application based on 
      this work (Tri-peptides and treatment of metabolic, cardiovascular, and 
      inflammatory disorders: PCT/US2019/046052). Y.E. Chen is the founder of Diapin 
      Therapeutics, which provided DT-109 for this study. All other authors declare 
      that they have no competing interests.
EDAT- 2022/04/22 06:00
MHDA- 2022/05/11 06:00
PMCR- 2022/04/13
CRDT- 2022/04/21 20:13
PHST- 2022/03/14 00:00 [received]
PHST- 2022/04/04 00:00 [revised]
PHST- 2022/04/08 00:00 [accepted]
PHST- 2022/04/22 06:00 [pubmed]
PHST- 2022/05/11 06:00 [medline]
PHST- 2022/04/21 20:13 [entrez]
PHST- 2022/04/13 00:00 [pmc-release]
AID - S2213-2317(22)00085-4 [pii]
AID - 102313 [pii]
AID - 10.1016/j.redox.2022.102313 [doi]
PST - ppublish
SO  - Redox Biol. 2022 Jun;52:102313. doi: 10.1016/j.redox.2022.102313. Epub 2022 Apr 
      13.