Gene-dosage effect of Pfkfb3 on monocyte/macrophage biology in atherosclerosis.
Gene-dosage effect of Pfkfb3 on monocyte/macrophage biology in atherosclerosis.
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DOI：
10.1111/bph.15926
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发表时间：
2022-11
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
富含巨噬细胞的动脉粥样硬化动脉在糖酵解中高度活跃。PFKFB 3是一种糖酵解关键酶，已成为动脉粥样硬化潜在的治疗靶点。PFKFB 3的小分子抑制剂，如3 PO和PFK 158，已在临床前模型中证实了阻碍动脉粥样硬化形成的功效。然而，需要进行阐明Pfkfb 3在动脉粥样硬化形成中的作用的遗传研究，以验证药理学发现并揭示潜在的药理学副作用。对具有全杂合子或骨髓细胞特异性Pfkfb 3缺陷的Apoe−/−小鼠喂食西方饮食（WD），然后确定动脉粥样硬化的发展。采用流式细胞术检测动脉粥样硬化小鼠和患者的单核细胞亚群。单核细胞浸润通过Ly 6Chi单核细胞特异性胶乳标记程序测定。在小鼠主动脉根部切片上评估原位红细胞增多。此外，还分析了腹腔巨噬细胞的代谢状态、巨噬细胞运动性、巨噬细胞增多症及其相关机制。全杂合子或骨髓细胞特异性Pfkfb 3缺陷减少Apoe−/−小鼠的动脉粥样硬化形成机制研究表明，PFKFB 3控制促炎单核细胞的增殖和浸润。此外，在动脉粥样硬化性冠状动脉疾病患者中，PFKFB 3表达与炎症单核细胞扩增相关。令人惊讶的是，Pfkfb 3的纯合缺失损害了Apoe−/−小鼠的巨噬细胞吞噬功能，并加剧了动脉粥样硬化。从机制上讲，PFKFB 3驱动的糖酵解被证明是必不可少的肌动蛋白聚合，从而帮助巨噬细胞的吞噬功能。总的来说，这些发现表明髓样PFKFB 3对动脉粥样硬化的发病机制存在双刃剑效应，并强调在开发靶向PFKFB 3的抗动脉粥样硬化策略时需要谨慎。
Macrophage-rich atherosclerotic arteries are highly active in glycolysis. PFKFB3, a key glycolytic enzyme, has emerged as a potential therapeutic target in atherosclerosis. Small-molecule inhibitors of PFKFB3, such as 3PO and PFK158, have demonstrated efficacy in hampering atherogenesis in preclinical models. However, genetic studies elucidating the role of Pfkfb3 in atherogenesis need to be conducted to validate pharmacological findings and to unveil potential pharmacological side effects. Apoe−/− mice with global heterozygous or myeloid cell-specific Pfkfb3 deficiency were fed a Western diet (WD), after which atherosclerosis development was determined. Monocyte subsets in atherosclerotic mice and patients were examined by flow cytometry. Monocyte infiltration was assayed by a Ly6Chi monocyte-specific latex labelling procedure. In situ efferocytosis was assessed on mouse aortic root sections. Additionally, metabolic status, macrophage motility, efferocytosis, and involved mechanisms were analysed in peritoneal macrophages. Global heterozygous or myeloid cell-specific Pfkfb3 deficiency reduced atherogenesis in Apoe−/− mice. Mechanistic studies showed that PFKFB3 controlled the proliferation and infiltration of proinflammatory monocytes. Moreover, PFKFB3 expression was associated with inflammatory monocyte expansion in patients with atherosclerotic coronary artery disease. Surprisingly, homozygous loss of Pfkfb3 impaired macrophage efferocytosis and exacerbated atherosclerosis in Apoe−/− mice. Mechanistically, PFKFB3-driven glycolysis was shown to be essential for actin polymerization, thus aiding the efferocytotic function of macrophages. Collectively, these findings suggest the existence of a double-edged sword effect of myeloid PFKFB3 on the pathogenesis of atherosclerosis and highlight the need for caution in developing anti-atherosclerotic strategies that target PFKFB3.
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DOI：
10.1161/atvbaha.115.305551
发表时间：
2015-06
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Tawakol A;Singh P;Mojena M;Pimentel-Santillana M;Emami H;MacNabb M;Rudd JH;Narula J;Enriquez JA;Través PG;Fernández-Velasco M;Bartrons R;Martín-Sanz P;Fayad ZA;Tejedor A;Boscá L
通讯作者：
Boscá L
影响因子：
20.1
作者：
Sarrazy V;Viaud M;Westerterp M;Ivanov S;Giorgetti-Peraldi S;Guinamard R;Gautier EL;Thorp EB;De Vivo DC;Yvan-Charvet L
通讯作者：
Yvan-Charvet L
影响因子：
64.8
作者：
Kojima Y;Volkmer JP;McKenna K;Civelek M;Lusis AJ;Miller CL;Direnzo D;Nanda V;Ye J;Connolly AJ;Schadt EE;Quertermous T;Betancur P;Maegdefessel L;Matic LP;Hedin U;Weissman IL;Leeper NJ
通讯作者：
Leeper NJ
影响因子：
44.1
作者：
通讯作者：
--
影响因子：
64.5
作者：
De Bock, Katrien;Georgiadou, Maria;Carmeliet, Peter
通讯作者：
Carmeliet, Peter