TY - JOUR
T1 - Partial Inhibition of the 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 (PFKFB3) Enzyme in Myeloid Cells Does Not Affect Atherosclerosis
AU - Tillie, Renée J. H. A.
AU - de Bruijn, Jenny
AU - Perales-Patón, Javier
AU - Temmerman, Lieve
AU - Ghosheh, Yanal
AU - van Kuijk, Kim
AU - Gijbels, Marion J.
AU - Carmeliet, Peter
AU - Ley, Klaus
AU - Saez-Rodriguez, Julio
AU - Sluimer, Judith C.
N1 - Funding Information: JS report grants from the Dutch Organization for Scientific Research (016.116.017 VENI fellowship, and VIDI fellowship 0.16.186.364), grants from Dekker senior postdoc fellowship of the Dutch Heart Foundation 2016T060, and the Fondation Leducq (15CVD04) during the conduct of the study. JS-R report grants from JRC for Computational Biomedicine partially funded by Bayer AG., during the conduct of the study; and grants from GSK, grants from Sanofi, personal fees from Travere Therapeutics, outside the submitted work. PC report grants from Methusalem funding (Flemish government) and an ERC Advanced Research Grant (EU-ERC743074). Publisher Copyright: Copyright © 2021 Tillie, De Bruijn, Perales-Patón, Temmerman, Ghosheh, Van Kuijk, Gijbels, Carmeliet, Ley, Saez-Rodriguez and Sluimer.
PY - 2021/8/12
Y1 - 2021/8/12
N2 - 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+/–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 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. 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. 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.
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+/–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 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. 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. 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.
KW - PFKFB3
KW - atherosclerosis
KW - dendritic cell
KW - glycolysis
KW - glycolysis inhibition
KW - macrophage
KW - myeloid cells
KW - neutrophil
UR - http://www.scopus.com/inward/record.url?scp=85118771371&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fcell.2021.695684
DO - https://doi.org/10.3389/fcell.2021.695684
M3 - Article
C2 - 34458258
SN - 2296-634X
VL - 9
JO - Frontiers in cell and developmental biology
JF - Frontiers in cell and developmental biology
M1 - 695684
ER -