Tillie Renée J H A, De Bruijn Jenny, Perales-Patón Javier, Temmerman Lieve, Ghosheh Yanal, Van Kuijk Kim, Gijbels Marion J, Carmeliet Peter, Ley Klaus, Saez-Rodriguez Julio, Sluimer Judith C
Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands.
Faculty of Medicine, Institute for Computational Biomedicine, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany.
Front Cell Dev Biol. 2021 Aug 12;9:695684. doi: 10.3389/fcell.2021.695684. eCollection 2021.
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 ( ) mice confers beneficial effects on plaque stability and alleviates cardiovascular disease burden compared to control mice ( ).
Analysis of atherosclerotic human and murine single-cell populations confirmed expression in myeloid cells, but also in lymphocytes, endothelial cells, fibroblasts and smooth muscle cells. and mice were fed a 0.25% cholesterol diet for 12 weeks. bone marrow-derived macrophages (BMDMs) showed 50% knockdown of mRNA. As expected based on partial glycolysis inhibition, extracellular acidification rate as a measure of glycolysis was partially reduced in compared to BMDMs. Unexpectedly, plaque and necrotic core size, as well as macrophage (MAC3), neutrophil (Ly6G) and collagen (Sirius Red) content were unchanged in advanced lesions. Similarly, early lesion plaque and necrotic core size and total plaque burden were unaffected.
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 -expressing cells in atherosclerosis might be responsible, such as DCs, smooth muscle cells or fibroblasts.
蛋白6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶-3（PFKFB3）是糖酵解通量的关键刺激因子。先前全身性、部分性PFKFB3抑制可降低总斑块负担并增加斑块稳定性。然而，尚不清楚是哪种细胞类型产生了这些积极作用。髓样细胞在动脉粥样硬化形成中起重要作用，并且主要依靠糖酵解供能。因此，我们研究了与对照小鼠相比，在（ ）小鼠中髓样细胞对PFKFB3介导的糖酵解的抑制是否对斑块稳定性产生有益影响并减轻心血管疾病负担。
对动脉粥样硬化的人和小鼠单细胞群体的分析证实（ ）在髓样细胞中表达，但在淋巴细胞、内皮细胞、成纤维细胞和平滑肌细胞中也有表达。（ ）和（ ）小鼠喂食0.25%胆固醇饮食12周。（ ）骨髓来源的巨噬细胞（BMDMs）显示（ ）mRNA敲低50%。基于部分糖酵解抑制的预期，与（ ）BMDMs相比，作为糖酵解指标的细胞外酸化率在（ ）中部分降低。出乎意料的是，在晚期（ ）病变中，斑块和坏死核心大小以及巨噬细胞（MAC3）、中性粒细胞（Ly6G）和胶原蛋白（天狼星红）含量未发生变化。同样，早期病变斑块和坏死核心大小以及总斑块负担也未受影响。
PFKFB3在髓样细胞中的部分敲低不影响晚期或早期病变中的动脉粥样硬化发展。先前报道的全身性、部分性PFKFB3抑制对病变稳定的积极作用似乎不是由单核细胞、巨噬细胞或中性粒细胞产生的。相反，动脉粥样硬化中其他表达（ ）的细胞可能起作用，如树突状细胞、平滑肌细胞或成纤维细胞。
