Poels Kikkie, Schnitzler Johan G, Waissi Farahnaz, Levels Johannes H M, Stroes Erik S G, Daemen Mat J A P, Lutgens Esther, Pennekamp Anne-Marije, De Kleijn Dominique P V, Seijkens Tom T P, Kroon Jeffrey
Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
Department of Experimental Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, Netherlands.
Front Cell Dev Biol. 2020 Nov 12;8:581641. doi: 10.3389/fcell.2020.581641. eCollection 2020.
6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)3-mediated glycolysis is pivotal in driving macrophage- and endothelial cell activation and thereby inflammation. Once activated, these cells play a crucial role in the progression of atherosclerosis. Here, we analyzed the expression of PFKFB3 in human atherosclerotic lesions and investigated the therapeutic potential of pharmacological inhibition of PFKFB3 in experimental atherosclerosis by using the glycolytic inhibitor PFK158.
PFKFB3 expression was higher in vulnerable human atheromatous carotid plaques when compared to stable fibrous plaques and predominantly expressed in plaque macrophages and endothelial cells. Analysis of advanced plaques of human coronary arteries revealed a positive correlation of PFKFB3 expression with necrotic core area. To further investigate the role of PFKFB3 in atherosclerotic disease progression, we treated 6-8 weeks old male mice. These mice were fed a high cholesterol diet for 13 weeks, of which they were treated for 5 weeks with the glycolytic inhibitor PFK158 to block PFKFB3 activity. The incidence of fibrous cap atheroma (advanced plaques) was reduced in PFK158-treated mice. Plaque phenotype altered markedly as both necrotic core area and intraplaque apoptosis decreased. This coincided with thickening of the fibrous cap and increased plaque stability after PFK158 treatment. Concomitantly, we observed a decrease in glycolysis in peripheral blood mononuclear cells compared to the untreated group, which alludes that changes in the intracellular metabolism of monocyte and macrophages is advantageous for plaque stabilization.
High PFKFB3 expression is associated with vulnerable atheromatous human carotid and coronary plaques. In mice, high PFKFB3 expression is also associated with a vulnerable plaque phenotype, whereas inhibition of PFKFB3 activity leads to plaque stabilization. This data implies that inhibition of inducible glycolysis may reduce inflammation, which has the ability to subsequently attenuate atherogenesis.
6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶（PFKFB）3介导的糖酵解在驱动巨噬细胞和内皮细胞活化进而引发炎症过程中起关键作用。一旦这些细胞被激活，它们在动脉粥样硬化的进展中发挥着至关重要的作用。在此，我们分析了PFKFB3在人类动脉粥样硬化病变中的表达，并通过使用糖酵解抑制剂PFK158研究了PFKFB3药理抑制在实验性动脉粥样硬化中的治疗潜力。
与稳定的纤维斑块相比，易损性人类动脉粥样硬化颈动脉斑块中PFKFB3表达更高，且主要在斑块巨噬细胞和内皮细胞中表达。对人类冠状动脉晚期斑块的分析显示，PFKFB3表达与坏死核心区域呈正相关。为进一步研究PFKFB3在动脉粥样硬化疾病进展中的作用，我们对6 - 8周龄雄性小鼠进行了处理。这些小鼠喂食高胆固醇饮食13周，其中用糖酵解抑制剂PFK158处理5周以阻断PFKFB3活性。PFK158处理的小鼠中纤维帽动脉粥样瘤（晚期斑块）的发生率降低。斑块表型明显改变，坏死核心区域和斑块内凋亡均减少。这与PFK158处理后纤维帽增厚和斑块稳定性增加相吻合。同时，与未处理组相比，我们观察到外周血单核细胞中的糖酵解减少，这表明单核细胞和巨噬细胞细胞内代谢的变化有利于斑块稳定。
PFKFB3高表达与易损性人类动脉粥样硬化颈动脉和冠状动脉斑块相关。在小鼠中，PFKFB3高表达也与易损斑块表型相关，而抑制PFKFB3活性可导致斑块稳定。这些数据表明抑制诱导性糖酵解可能减轻炎症，进而有能力减弱动脉粥样硬化的发生。
