PMID- 32641587
OWN - NLM
STAT- MEDLINE
DCOM- 20210609
LR  - 20240329
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 5
IP  - 13
DP  - 2020 Jul 9
TI  - RAGE impairs murine diabetic atherosclerosis regression and implicates IRF7 in 
      macrophage inflammation and cholesterol metabolism.
LID - 137289 [pii]
LID - 10.1172/jci.insight.137289 [doi]
LID - e137289
AB  - Despite advances in lipid-lowering therapies, people with diabetes continue to 
      experience more limited cardiovascular benefits. In diabetes, hyperglycemia 
      sustains inflammation and preempts vascular repair. We tested the hypothesis that 
      the receptor for advanced glycation end-products (RAGE) contributes to these 
      maladaptive processes. We report that transplantation of aortic arches from 
      diabetic, Western diet-fed Ldlr-/- mice into diabetic Ager-/- (Ager, the gene 
      encoding RAGE) versus WT diabetic recipient mice accelerated regression of 
      atherosclerosis. RNA-sequencing experiments traced RAGE-dependent mechanisms 
      principally to the recipient macrophages and linked RAGE to interferon signaling. 
      Specifically, deletion of Ager in the regressing diabetic plaques downregulated 
      interferon regulatory factor 7 (Irf7) in macrophages. Immunohistochemistry 
      studies colocalized IRF7 and macrophages in both murine and human atherosclerotic 
      plaques. In bone marrow-derived macrophages (BMDMs), RAGE ligands upregulated 
      expression of Irf7, and in BMDMs immersed in a cholesterol-rich environment, 
      knockdown of Irf7 triggered a switch from pro- to antiinflammatory gene 
      expression and regulated a host of genes linked to cholesterol efflux and 
      homeostasis. Collectively, this work adds a new dimension to the immunometabolic 
      sphere of perturbations that impair regression of established diabetic 
      atherosclerosis and suggests that targeting RAGE and IRF7 may facilitate vascular 
      repair in diabetes.
FAU - Senatus, Laura
AU  - Senatus L
AD  - Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, 
      Department of Medicine.
FAU - Lopez-Diez, Raquel
AU  - Lopez-Diez R
AD  - Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, 
      Department of Medicine.
FAU - Egana-Gorrono, Lander
AU  - Egana-Gorrono L
AD  - Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, 
      Department of Medicine.
FAU - Liu, Jianhua
AU  - Liu J
AD  - Marc and Ruti Bell Program in Vascular Biology, Leon H. Charney Division of 
      Cardiology, Department of Medicine.
FAU - Hu, Jiyuan
AU  - Hu J
AD  - Division of Biostatistics, Department of Population Health, and Department of 
      Environmental Medicine, and.
FAU - Daffu, Gurdip
AU  - Daffu G
AD  - Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, 
      Department of Medicine.
FAU - Li, Qing
AU  - Li Q
AD  - Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, 
      Department of Medicine.
FAU - Rahman, Karishma
AU  - Rahman K
AD  - Marc and Ruti Bell Program in Vascular Biology, Leon H. Charney Division of 
      Cardiology, Department of Medicine.
FAU - Vengrenyuk, Yuliya
AU  - Vengrenyuk Y
AD  - Marc and Ruti Bell Program in Vascular Biology, Leon H. Charney Division of 
      Cardiology, Department of Medicine.
FAU - Barrett, Tessa J
AU  - Barrett TJ
AD  - Marc and Ruti Bell Program in Vascular Biology, Leon H. Charney Division of 
      Cardiology, Department of Medicine.
FAU - Dewan, M Zahidunnabi
AU  - Dewan MZ
AD  - Experimental Pathology Research Laboratory, Department of Pathology, New York 
      University (NYU) Langone Medical Center, New York, New York, USA.
FAU - Guo, Liang
AU  - Guo L
AD  - CVPath Institute, Gaithersburg, Maryland, USA.
FAU - Fuller, Daniela
AU  - Fuller D
AD  - CVPath Institute, Gaithersburg, Maryland, USA.
FAU - Finn, Aloke V
AU  - Finn AV
AD  - CVPath Institute, Gaithersburg, Maryland, USA.
FAU - Virmani, Renu
AU  - Virmani R
AD  - CVPath Institute, Gaithersburg, Maryland, USA.
FAU - Li, Huilin
AU  - Li H
AD  - Division of Biostatistics, Department of Population Health, and Department of 
      Environmental Medicine, and.
FAU - Friedman, Richard A
AU  - Friedman RA
AD  - Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer 
      Center, and Department of Biomedical Informatics, Columbia University Irving 
      Medical Center, New York, New York, USA.
FAU - Fisher, Edward A
AU  - Fisher EA
AD  - Marc and Ruti Bell Program in Vascular Biology, Leon H. Charney Division of 
      Cardiology, Department of Medicine.
FAU - Ramasamy, Ravichandran
AU  - Ramasamy R
AD  - Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, 
      Department of Medicine.
FAU - Schmidt, Ann Marie
AU  - Schmidt AM
AD  - Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, 
      Department of Medicine.
LA  - eng
GR  - P01 HL131481/HL/NHLBI NIH HHS/United States
GR  - R01 HL136314/HL/NHLBI NIH HHS/United States
GR  - P01 HL146367/HL/NHLBI NIH HHS/United States
GR  - R01 HL141425/HL/NHLBI NIH HHS/United States
GR  - R01 HL132516/HL/NHLBI NIH HHS/United States
GR  - R01 HL084312/HL/NHLBI NIH HHS/United States
GR  - P30 CA016087/CA/NCI NIH HHS/United States
GR  - 17SFRN33490004/AHA/American Heart Association-American Stroke Association/United 
      States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200709
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - 0 (AGER protein, human)
RN  - 0 (IRF7 protein, human)
RN  - 0 (Interferon Regulatory Factor-7)
RN  - 0 (Irf7 protein, mouse)
RN  - 0 (Receptor for Advanced Glycation End Products)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Animals
MH  - Atherosclerosis/*metabolism
MH  - Cholesterol/*metabolism
MH  - Humans
MH  - Inflammation/*metabolism
MH  - Interferon Regulatory Factor-7/*metabolism
MH  - Macrophages/*metabolism
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Receptor for Advanced Glycation End Products/genetics/metabolism
PMC - PMC7406264
OTO - NOTNLM
OT  - Atherosclerosis
OT  - Diabetes
OT  - Inflammation
OT  - Innate immunity
OT  - Vascular Biology
COIS- Conflict of interest: AMS and RR are inventors on awarded (US 9,353,3078, US 
      9364472) and pending (US 16/094270, Europe 177864360.0) patent applications 
      assigned to NYU Grossman Medical Center. EAF served as an expert witness on a 
      patent case involving fish oils and received NIH funding. AVF and RV have 
      grant/research/clinical trial support from Leducq Foundation Grant; 480 
      Biomedical; 4C Medical; 4Tech; Abbott; Accu Medical Inc.; Amgen; Biosensors; 
      Boston Scientific; Cardiac Implants; CeloNova Biosciences; Claret Medical; 
      Concept Medical; Cook; CSI; DuNing, Inc.; Edwards Lifesciences; Emboline; 
      Endotronix; Envision Scientific; Lutonix, BD; Gateway; LifeTech Scientific 
      Corporation; LimFlow; MedAlliance; Medtronic; Mercator; Merill; Microport 
      Medical; Microvention; Mitralign; MitrAssist; NAMSA; Nanova, Inc.; Neovasc; 
      NIPRO; Novogate Medical; Occlutech; OrbusNeich Medical; Phenox; Profusa; 
      Protembis; Qool; ReCor Medical; Senseonics; Shockwave; Sino Medical Sciences 
      Technology Inc.; Spectranetics; Surmodics; Symic; Vesper; W.L. Gore; and Xeltis. 
      AVF has served Abbott Vascular (speaker's bureau [SB] and consultant/advisory 
      board [CAB]); Amgen (CAB); Biosensors (SB); Boston Scientific (SB and CAB); 
      CeloNova Biosciences (SB and CAB); Cook Medical (SB and CAB); CSI (SB); Lutonix, 
      BD (SB and CAB); Sino Medical Sciences Technology Inc. (SB and CAB); and Terumo 
      Corporation (SB). RV has served Abbott Vascular (SB and CAB); Biosensors (SB); 
      Boston Scientific; CeloNova Biosciences; Cook Medical; Cordis; CSI (SB and CAB 
      for previous 5); Edwards Lifescience (CAB); Lutonix, BD; Medtronic; OrbusNeich 
      Medical; ReCor Medical; Sino Medical Sciences Technology Inc.; Spectranetics (SB 
      and CAB for previous 6); Surmodics (CAB); Terumo Corporation (SB and CAB); W.L. 
      Gore (SB and CAB); and Xeltis (CAB).
EDAT- 2020/07/10 06:00
MHDA- 2021/06/10 06:00
PMCR- 2020/07/09
CRDT- 2020/07/10 06:00
PHST- 2020/02/24 00:00 [received]
PHST- 2020/05/21 00:00 [accepted]
PHST- 2020/07/10 06:00 [entrez]
PHST- 2020/07/10 06:00 [pubmed]
PHST- 2021/06/10 06:00 [medline]
PHST- 2020/07/09 00:00 [pmc-release]
AID - 137289 [pii]
AID - 10.1172/jci.insight.137289 [doi]
PST - epublish
SO  - JCI Insight. 2020 Jul 9;5(13):e137289. doi: 10.1172/jci.insight.137289.