Partial Inhibition of the 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 (PFKFB3) Enzyme in Myeloid Cells Does Not Affect Atherosclerosis
BackgroundThe 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 e...
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Frontiers Media S.A.
2021-08-01
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| author | Renée J. H. A. Tillie Jenny De Bruijn Javier Perales-Patón Javier Perales-Patón Lieve Temmerman Yanal Ghosheh Kim Van Kuijk Marion J. Gijbels Marion J. Gijbels Marion J. Gijbels Peter Carmeliet Peter Carmeliet Peter Carmeliet Klaus Ley Klaus Ley Julio Saez-Rodriguez Julio Saez-Rodriguez Judith C. Sluimer Judith C. Sluimer |
| author_facet | Renée J. H. A. Tillie Jenny De Bruijn Javier Perales-Patón Javier Perales-Patón Lieve Temmerman Yanal Ghosheh Kim Van Kuijk Marion J. Gijbels Marion J. Gijbels Marion J. Gijbels Peter Carmeliet Peter Carmeliet Peter Carmeliet Klaus Ley Klaus Ley Julio Saez-Rodriguez Julio Saez-Rodriguez Judith C. Sluimer Judith C. Sluimer |
| author_sort | Renée J. H. A. Tillie |
| collection | DOAJ |
| description | BackgroundThe 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+/–Pfkfb3fl/fl (Pfkfb3fl/fl) mice confers beneficial effects on plaque stability and alleviates cardiovascular disease burden compared to Ldlr–/–LysMCre+/–Pfkfb3wt/wt control mice (Pfkfb3wt/wt).Methods and ResultsAnalysis 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. Pfkfb3wt/wt and Pfkfb3fl/fl mice were fed a 0.25% cholesterol diet for 12 weeks. Pfkfb3fl/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 Pfkfb3fl/fl compared to Pfkfb3wt/wt BMDMs. Unexpectedly, plaque and necrotic core size, as well as macrophage (MAC3), neutrophil (Ly6G) and collagen (Sirius Red) content were unchanged in advanced Pfkfb3fl/fl lesions. Similarly, early lesion plaque and necrotic core size and total plaque burden were unaffected.ConclusionPartial 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. |
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| spelling | doaj.art-e67d4abce7b348689fd4c1dd221374ce2022-12-21T18:20:37ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-08-01910.3389/fcell.2021.695684695684Partial Inhibition of the 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 (PFKFB3) Enzyme in Myeloid Cells Does Not Affect AtherosclerosisRenée J. H. A. Tillie0Jenny De Bruijn1Javier Perales-Patón2Javier Perales-Patón3Lieve Temmerman4Yanal Ghosheh5Kim Van Kuijk6Marion J. Gijbels7Marion J. Gijbels8Marion J. Gijbels9Peter Carmeliet10Peter Carmeliet11Peter Carmeliet12Klaus Ley13Klaus Ley14Julio Saez-Rodriguez15Julio Saez-Rodriguez16Judith C. Sluimer17Judith C. Sluimer18Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, NetherlandsDepartment of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, NetherlandsFaculty of Medicine, Institute for Computational Biomedicine, Heidelberg University Hospital, Heidelberg University, Heidelberg, GermanyInstitute of Experimental Medicine and Systems Biology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, GermanyDepartment of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, NetherlandsLa Jolla Institute for Immunology, San Diego, CA, United StatesDepartment of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, NetherlandsDepartment of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, NetherlandsDepartment of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, NetherlandsDepartment of Medical Biochemistry, Experimental Vascular Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsLaboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Center for Cancer Biology, Vlaams Instituut voor Biotechnologie (VIB), Leuven Cancer Institute, KU Leuven, Leuven, BelgiumState Key Laboratory of Ophthalmology, Zhongshan Opthalmic Center, Sun Yat-sen University, Guangzhou, ChinaDepartment of Biomedicine, Aarhus University, Aarhus, DenmarkLa Jolla Institute for Immunology, San Diego, CA, United States0Department of Bioengineering, University of California, San Diego, San Diego, CA, United StatesFaculty of Medicine, Institute for Computational Biomedicine, Heidelberg University Hospital, Heidelberg University, Heidelberg, GermanyInstitute of Experimental Medicine and Systems Biology, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, GermanyDepartment of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands1British Heart Foundation (BHF) Centre for Cardiovascular Sciences (CVS), University of Edinburgh, Edinburgh, United KingdomBackgroundThe 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+/–Pfkfb3fl/fl (Pfkfb3fl/fl) mice confers beneficial effects on plaque stability and alleviates cardiovascular disease burden compared to Ldlr–/–LysMCre+/–Pfkfb3wt/wt control mice (Pfkfb3wt/wt).Methods and ResultsAnalysis 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. Pfkfb3wt/wt and Pfkfb3fl/fl mice were fed a 0.25% cholesterol diet for 12 weeks. Pfkfb3fl/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 Pfkfb3fl/fl compared to Pfkfb3wt/wt BMDMs. Unexpectedly, plaque and necrotic core size, as well as macrophage (MAC3), neutrophil (Ly6G) and collagen (Sirius Red) content were unchanged in advanced Pfkfb3fl/fl lesions. Similarly, early lesion plaque and necrotic core size and total plaque burden were unaffected.ConclusionPartial 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.https://www.frontiersin.org/articles/10.3389/fcell.2021.695684/fullmyeloid cellsPFKFB3macrophagedendritic cellglycolysisatherosclerosis |
| spellingShingle | Renée J. H. A. Tillie Jenny De Bruijn Javier Perales-Patón Javier Perales-Patón Lieve Temmerman Yanal Ghosheh Kim Van Kuijk Marion J. Gijbels Marion J. Gijbels Marion J. Gijbels Peter Carmeliet Peter Carmeliet Peter Carmeliet Klaus Ley Klaus Ley Julio Saez-Rodriguez Julio Saez-Rodriguez Judith C. Sluimer Judith C. Sluimer Partial Inhibition of the 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 (PFKFB3) Enzyme in Myeloid Cells Does Not Affect Atherosclerosis Frontiers in Cell and Developmental Biology myeloid cells PFKFB3 macrophage dendritic cell glycolysis atherosclerosis |
| title | Partial Inhibition of the 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 (PFKFB3) Enzyme in Myeloid Cells Does Not Affect Atherosclerosis |
| title_full | Partial Inhibition of the 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 (PFKFB3) Enzyme in Myeloid Cells Does Not Affect Atherosclerosis |
| title_fullStr | Partial Inhibition of the 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 (PFKFB3) Enzyme in Myeloid Cells Does Not Affect Atherosclerosis |
| title_full_unstemmed | Partial Inhibition of the 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 (PFKFB3) Enzyme in Myeloid Cells Does Not Affect Atherosclerosis |
| title_short | Partial Inhibition of the 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 (PFKFB3) Enzyme in Myeloid Cells Does Not Affect Atherosclerosis |
| title_sort | partial inhibition of the 6 phosphofructo 2 kinase fructose 2 6 bisphosphatase 3 pfkfb3 enzyme in myeloid cells does not affect atherosclerosis |
| topic | myeloid cells PFKFB3 macrophage dendritic cell glycolysis atherosclerosis |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.695684/full |
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