PMID- 34458258
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220426
IS  - 2296-634X (Print)
IS  - 2296-634X (Electronic)
IS  - 2296-634X (Linking)
VI  - 9
DP  - 2021
TI  - Partial Inhibition of the 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 
      (PFKFB3) Enzyme in Myeloid Cells Does Not Affect Atherosclerosis.
PG  - 695684
LID - 10.3389/fcell.2021.695684 [doi]
LID - 695684
AB  - BACKGROUND: The protein 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 
      (PFKFB3) is a key stimulator of glycolytic flux. Systemic, partial PFKFB3 
      inhibition previously decreased total plaque burden and increased plaque 
      stability. However, it is unclear which cell type conferred these positive 
      effects. Myeloid cells play an important role in atherogenesis, and mainly rely 
      on glycolysis for energy supply. Thus, we studied whether myeloid inhibition of 
      PFKFB3-mediated glycolysis in Ldlr(-/-)LysMCre(+/-)Pfkfb3 (fl/fl) (Pfkfb3 (fl/fl) 
      ) mice confers beneficial effects on plaque stability and alleviates 
      cardiovascular disease burden compared to Ldlr(-/-)LysMCre(+/-)Pfkfb3 (wt/wt) 
      control mice (Pfkfb3 (wt/wt) ). METHODS AND RESULTS: Analysis of atherosclerotic 
      human and murine single-cell populations confirmed PFKFB3/Pfkfb3 expression in 
      myeloid cells, but also in lymphocytes, endothelial cells, fibroblasts and smooth 
      muscle cells. Pfkfb3 (wt/wt) and Pfkfb3 (fl/fl) mice were fed a 0.25% cholesterol 
      diet for 12 weeks. Pfkfb3 (fl/fl) bone marrow-derived macrophages (BMDMs) showed 
      50% knockdown of Pfkfb3 mRNA. As expected based on partial glycolysis inhibition, 
      extracellular acidification rate as a measure of glycolysis was partially reduced 
      in Pfkfb3 (fl/fl) compared to Pfkfb3 (wt/wt) BMDMs. Unexpectedly, plaque and 
      necrotic core size, as well as macrophage (MAC3), neutrophil (Ly6G) and collagen 
      (Sirius Red) content were unchanged in advanced Pfkfb3 (fl/fl) lesions. 
      Similarly, early lesion plaque and necrotic core size and total plaque burden 
      were unaffected. CONCLUSION: Partial myeloid knockdown of PFKFB3 did not affect 
      atherosclerosis development in advanced or early lesions. Previously reported 
      positive effects of systemic, partial PFKFB3 inhibition on lesion stabilization, 
      do not seem conferred by monocytes, macrophages or neutrophils. Instead, other 
      Pfkfb3-expressing cells in atherosclerosis might be responsible, such as DCs, 
      smooth muscle cells or fibroblasts.
CI  - Copyright (c) 2021 Tillie, De Bruijn, Perales-Paton, Temmerman, Ghosheh, Van Kuijk, 
      Gijbels, Carmeliet, Ley, Saez-Rodriguez and Sluimer.
FAU - Tillie, Renee J H A
AU  - Tillie RJHA
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Center, Maastricht, Netherlands.
FAU - De Bruijn, Jenny
AU  - De Bruijn J
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Center, Maastricht, Netherlands.
FAU - Perales-Paton, Javier
AU  - Perales-Paton J
AD  - Faculty of Medicine, Institute for Computational Biomedicine, Heidelberg 
      University Hospital, Heidelberg University, Heidelberg, Germany.
AD  - Institute of Experimental Medicine and Systems Biology, Rheinisch-Westfalische 
      Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
FAU - Temmerman, Lieve
AU  - Temmerman L
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Center, Maastricht, Netherlands.
FAU - Ghosheh, Yanal
AU  - Ghosheh Y
AD  - La Jolla Institute for Immunology, San Diego, CA, United States.
FAU - Van Kuijk, Kim
AU  - Van Kuijk K
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Center, Maastricht, Netherlands.
FAU - Gijbels, Marion J
AU  - Gijbels MJ
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Center, Maastricht, Netherlands.
AD  - Department of Pathology, GROW-School for Oncology and Developmental Biology, 
      Maastricht University Medical Center, Maastricht, Netherlands.
AD  - Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam UMC, 
      University of Amsterdam, Amsterdam, Netherlands.
FAU - Carmeliet, Peter
AU  - Carmeliet P
AD  - Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, 
      Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven 
      Cancer Institute, KU Leuven, Leuven, Belgium.
AD  - State Key Laboratory of Ophthalmology, Zhongshan Opthalmic Center, Sun Yat-sen 
      University, Guangzhou, China.
AD  - Department of Biomedicine, Aarhus University, Aarhus, Denmark.
FAU - Ley, Klaus
AU  - Ley K
AD  - La Jolla Institute for Immunology, San Diego, CA, United States.
AD  - Department of Bioengineering, University of California, San Diego, San Diego, CA, 
      United States.
FAU - Saez-Rodriguez, Julio
AU  - Saez-Rodriguez J
AD  - Faculty of Medicine, Institute for Computational Biomedicine, Heidelberg 
      University Hospital, Heidelberg University, Heidelberg, Germany.
AD  - Institute of Experimental Medicine and Systems Biology, Rheinisch-Westfalische 
      Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
FAU - Sluimer, Judith C
AU  - Sluimer JC
AD  - Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), 
      Maastricht University Medical Center, Maastricht, Netherlands.
AD  - British Heart Foundation (BHF) Centre for Cardiovascular Sciences (CVS), 
      University of Edinburgh, Edinburgh, United Kingdom.
LA  - eng
PT  - Journal Article
DEP - 20210812
PL  - Switzerland
TA  - Front Cell Dev Biol
JT  - Frontiers in cell and developmental biology
JID - 101630250
PMC - PMC8387953
OTO - NOTNLM
OT  - PFKFB3
OT  - atherosclerosis
OT  - dendritic cell
OT  - glycolysis
OT  - glycolysis inhibition
OT  - macrophage
OT  - myeloid cells
OT  - neutrophil
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/08/31 06:00
MHDA- 2021/08/31 06:01
PMCR- 2021/01/01
CRDT- 2021/08/30 06:01
PHST- 2021/04/15 00:00 [received]
PHST- 2021/07/26 00:00 [accepted]
PHST- 2021/08/30 06:01 [entrez]
PHST- 2021/08/31 06:00 [pubmed]
PHST- 2021/08/31 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fcell.2021.695684 [doi]
PST - epublish
SO  - Front Cell Dev Biol. 2021 Aug 12;9:695684. doi: 10.3389/fcell.2021.695684. 
      eCollection 2021.