PMID- 35032419
OWN - NLM
STAT- MEDLINE
DCOM- 20220214
LR  - 20220214
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 36
IP  - 2
DP  - 2022 Feb
TI  - Eukaryotic elongation factor 2 kinase regulates foam cell formation via 
      translation of CD36.
PG  - e22154
LID - 10.1096/fj.202101034R [doi]
AB  - Eukaryotic elongation factor 2 kinase (eEF2K) is an atypical protein kinase that 
      controls protein synthesis in cells under stress. Although well studied in 
      cancer, less is known about its roles in chronic inflammatory diseases. Here, we 
      examined its regulation of macrophage cholesterol handling in the context of 
      atherosclerosis. eEF2K mRNA expression and protein activity were upregulated in 
      murine bone marrow-derived macrophages (BMDMs) exposed to oxidized low-density 
      lipoprotein cholesterol (oxLDL). When incubated with oxLDL, BMDMs from eEF2K 
      knockout (Eef2k(-/-) ) mice formed fewer Oil Red O(+) foam cells than Eef2k(+/+) 
      BMDMs (12.5% +/- 2.3% vs. 32.3% +/- 2.0%, p < .01). Treatment with a selective eEF2K 
      inhibitor, JAN-384, also decreased foam cell formation for C57BL/6J BMDMs and 
      human monocyte-derived macrophages. Disabling eEF2K selectively decreased protein 
      expression of the CD36 cholesterol uptake receptor, mediated by a reduction in 
      the proportion of translationally active Cd36 mRNA. Eef2k(-/-) mice bred onto the 
      Ldlr(-/-) background developed aortic sinus atherosclerotic plaques that were 30% 
      smaller than Eef2k(+/+) -Ldlr(-/-) mice after 16 weeks of high cholesterol diet 
      (p < .05). Although accompanied by a reduction in plaque CD36(+) staining 
      (p < .05) and lower CD36 expression in circulating monocytes (p < .01), this was 
      not associated with reduced lipid content in plaques as measured by oil red O 
      staining. Finally, EEF2K and CD36 mRNA levels were higher in blood mononuclear 
      cells from patients with coronary artery disease and recent myocardial infarction 
      compared to healthy controls without coronary artery disease. These results 
      reveal a new role for eEF2K in translationally regulating CD36 expression and 
      foam cell formation in macrophages. Further studies are required to explore 
      therapeutic targeting of eEF2K in atherosclerosis.
CI  - (c) 2022 Federation of American Societies for Experimental Biology.
FAU - Fernando, Sanuja
AU  - Fernando S
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
AD  - Adelaide Medical School, University of Adelaide, Adelaide, South Australia, 
      Australia.
FAU - Salagaras, Thalia
AU  - Salagaras T
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
FAU - Schwarz, Nisha
AU  - Schwarz N
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
FAU - Sandeman, Lauren
AU  - Sandeman L
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
AD  - Adelaide Medical School, University of Adelaide, Adelaide, South Australia, 
      Australia.
FAU - Tan, Joanne T M
AU  - Tan JTM
AUID- ORCID: 0000-0003-1875-4882
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
AD  - Adelaide Medical School, University of Adelaide, Adelaide, South Australia, 
      Australia.
FAU - Xie, Jianling
AU  - Xie J
AD  - Lifelong Health in Nutrition and Metabolism, Lifelong Health Theme, South 
      Australian Health and Medical Research Institute, Adelaide, South Australia, 
      Australia.
FAU - Zareh, Jonar
AU  - Zareh J
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
FAU - Jensen, Kirk
AU  - Jensen K
AD  - Lifelong Health in Nutrition and Metabolism, Lifelong Health Theme, South 
      Australian Health and Medical Research Institute, Adelaide, South Australia, 
      Australia.
FAU - Williamson, Anna
AU  - Williamson A
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
AD  - Adelaide Medical School, University of Adelaide, Adelaide, South Australia, 
      Australia.
FAU - Dimasi, Catherine
AU  - Dimasi C
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
FAU - Chhay, Pich
AU  - Chhay P
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
FAU - Toledo-Flores, Deborah
AU  - Toledo-Flores D
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
FAU - Long, Aaron
AU  - Long A
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
FAU - Manavis, Jim
AU  - Manavis J
AD  - Adelaide Medical School, University of Adelaide, Adelaide, South Australia, 
      Australia.
FAU - Worthington, Michael
AU  - Worthington M
AD  - Department of Cardiothoracic Surgery, Royal Adelaide Hospital, Central Adelaide 
      Local Health Network, Adelaide, South Australia, Australia.
FAU - Fitridge, Robert
AU  - Fitridge R
AD  - Adelaide Medical School, University of Adelaide, Adelaide, South Australia, 
      Australia.
AD  - Department of Vascular Surgery, Royal Adelaide Hospital, Central Adelaide Local 
      Health Network, Adelaide, South Australia, Australia.
FAU - Di Bartolo, Belinda A
AU  - Di Bartolo BA
AD  - The Kolling Institute, The University of Sydney, Sydney, New South Wales, 
      Australia.
FAU - Bursill, Christina A
AU  - Bursill CA
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
AD  - Adelaide Medical School, University of Adelaide, Adelaide, South Australia, 
      Australia.
FAU - Nicholls, Stephen J
AU  - Nicholls SJ
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
AD  - Monash Cardiovascular Research Centre, Monash University, Melbourne, Victoria, 
      Australia.
FAU - Proud, Christopher G
AU  - Proud CG
AD  - Lifelong Health in Nutrition and Metabolism, Lifelong Health Theme, South 
      Australian Health and Medical Research Institute, Adelaide, South Australia, 
      Australia.
AD  - School of Biological Sciences, University of Adelaide, Adelaide, South Australia, 
      Australia.
FAU - Psaltis, Peter J
AU  - Psaltis PJ
AUID- ORCID: 0000-0003-0222-5468
AD  - Vascular Research Centre, Heart and Vascular Program, Lifelong Health Theme, 
      South Australian Health and Medical Research Institute, Adelaide, South 
      Australia, Australia.
AD  - Adelaide Medical School, University of Adelaide, Adelaide, South Australia, 
      Australia.
AD  - Department of Cardiology, Royal Adelaide Hospital, Central Adelaide Local Health 
      Network, Adelaide, South Australia, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 0 (CD36 Antigens)
RN  - 0 (RNA, Messenger)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 2.7.11.20 (Eef2k protein, mouse)
RN  - EC 2.7.11.20 (Elongation Factor 2 Kinase)
SB  - IM
MH  - Animals
MH  - Atherosclerosis/metabolism
MH  - CD36 Antigens/*metabolism
MH  - Cholesterol/metabolism
MH  - Coronary Artery Disease/metabolism
MH  - Elongation Factor 2 Kinase/*metabolism
MH  - Female
MH  - Foam Cells/*metabolism
MH  - Humans
MH  - Leukocytes, Mononuclear/metabolism
MH  - Macrophages/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Monocytes/metabolism
MH  - Plaque, Atherosclerotic/metabolism
MH  - RNA, Messenger/metabolism
MH  - Signal Transduction/physiology
OTO - NOTNLM
OT  - CD36
OT  - atherosclerosis
OT  - eEF2K
OT  - foam cells
OT  - macrophages
OT  - protein translation
EDAT- 2022/01/16 06:00
MHDA- 2022/02/15 06:00
CRDT- 2022/01/15 17:05
PHST- 2021/12/14 00:00 [revised]
PHST- 2021/06/24 00:00 [received]
PHST- 2021/12/27 00:00 [accepted]
PHST- 2022/01/15 17:05 [entrez]
PHST- 2022/01/16 06:00 [pubmed]
PHST- 2022/02/15 06:00 [medline]
AID - 10.1096/fj.202101034R [doi]
PST - ppublish
SO  - FASEB J. 2022 Feb;36(2):e22154. doi: 10.1096/fj.202101034R.