Abstract
Aims6-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.Methods and ResultsPFKFB3 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 Ldlr–/– 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.ConclusionHigh 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.
Highlights
In recent years it has become clear that the development of atherosclerosis coincides with marked metabolic cellular alterations (Ali et al, 2018; Riksen and Stienstra, 2018)
Higher PFKFB3 expression coincides with high number of CD68+ macrophage in atheromatous plaques (Figures 1A,C) that positively correlates with PFKFB3 expression (Figure 1D)
These data imply that mainly macrophages show enhanced PFKFB3 expression in atherosclerotic plaques
Summary
In recent years it has become clear that the development of atherosclerosis coincides with marked metabolic cellular alterations (Ali et al, 2018; Riksen and Stienstra, 2018). Inflammatory stimuli modify the intracellular metabolism of multiple cell types involved in atherogenesis, such as macrophages and endothelial cells These cells are highly dependent on glycolysis for their energy metabolism to regulate cellular function (Bekkering et al, 2018; Riksen and Stienstra, 2018; Schnitzler et al, 2020). Lipid-lowering strategies markedly reduce cardiovascular event rates; a residual inflammatory risk remains even after potent lipid-lowering therapy in patients (Ridker, 2016; Stiekema et al, 2019) Atherogenic stimuli such as Lp(a) have been shown to induce endothelial cell activation through upregulation of keyglycolytic players comprising glucose transporter (GLUT) 1 and hexokinase (Hk) II (Schnitzler et al, 2020). Partial glycolytic inhibition in Apoe−/− mice via silencing of PFKFB3 results in decreased glycolysis in the arterial wall (Tawakol et al, 2015). It is currently not known how glycolytic inhibition affects the progression of atherosclerosis
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