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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.

Partial Inhibition of the 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 (PFKFB3) Enzyme in Myeloid Cells Does Not Affect Atherosclerosis