RATIONALE Patients with elevated levels of lipoprotein(a) [Lp(a)] are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of a proinflammatory state. OBJECTIVE We hypothesized that Lp(a) induces endothelial cell inflammation by rewiring endothelial metabolism. METHODS AND RESULTS We evaluated the impact of Lp(a) on the endothelium and describe that Lp(a), through its oxidized phospholipid content, activates arterial endothelial cells, facilitating increased transendothelial migration of monocytes. Transcriptome analysis of Lp(a)-stimulated human arterial endothelial cells revealed upregulation of inflammatory pathways comprising monocyte adhesion and migration, coinciding with increased 6-phophofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)-3-mediated glycolysis. ICAM (intercellular adhesion molecule)-1 and PFKFB3 were also found to be upregulated in carotid plaques of patients with elevated levels of Lp(a). Inhibition of PFKFB3 abolished the inflammatory signature with concomitant attenuation of transendothelial migration. CONCLUSIONS Collectively, our findings show that Lp(a) activates the endothelium by enhancing PFKFB3-mediated glycolysis, leading to a proadhesive state, which can be reversed by inhibition of glycolysis. These findings pave the way for therapeutic agents targeting metabolism aimed at reducing inflammation in patients with cardiovascular disease.

中文翻译：

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致脂蛋白（a）增加血管糖酵解，从而促进炎症和白细胞外渗。

理由：在正电子发射断层扫描/计算机断层扫描中，脂蛋白（a）[Lp（a）]水平升高的患者的动脉壁代谢活动增加，标志着炎症状态。目的我们假设Lp（a）通过重新连接内皮代谢来诱导内皮细胞炎症。方法和结果我们评估了Lp（a）对内皮的影响，并描述了Lp（a）通过其氧化的磷脂含量激活动脉内皮细胞，从而促进单核细胞的跨内皮迁移。Lp（a）刺激的人类动脉内皮细胞的转录组分析显示上调的炎症途径，包括单核细胞粘附和迁移，与增加的6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶（PFKFB）-3-介导的糖酵解相吻合。LCAM（a）水平升高的患者颈动脉斑块中的ICAM（细胞间粘附分子）-1和PFKFB3也被上调。PFKFB3的抑制消除了炎症特征，并伴随着跨内皮迁移的减弱。结论总体而言，我们的研究结果表明Lp（a）通过增强PFKFB3介导的糖酵解作用激活内皮，导致前粘状态，可以通过抑制糖酵解作用来逆转。这些发现为靶向代谢的治疗药物铺平了道路，这些药物旨在减少心血管疾病患者的炎症。PFKFB3的抑制消除了炎症特征，并伴随着跨内皮迁移的减弱。结论总体而言，我们的研究结果表明Lp（a）通过增强PFKFB3介导的糖酵解作用激活内皮，导致前粘状态，可以通过抑制糖酵解作用来逆转。这些发现为靶向代谢的治疗药物铺平了道路，这些药物旨在减少心血管疾病患者的炎症。PFKFB3的抑制消除了炎症特征，并伴随着跨内皮迁移的减弱。结论总体而言，我们的研究结果表明Lp（a）通过增强PFKFB3介导的糖酵解作用激活内皮，导致前粘状态，可以通过抑制糖酵解作用来逆转。这些发现为靶向代谢的治疗药物铺平了道路，这些药物旨在减少心血管疾病患者的炎症。