Myeloid Cell PKM2 Deletion Enhances Efferocytosis and Reduces Atherosclerosis.
Myeloid Cell PKM2 Deletion Enhances Efferocytosis and Reduces Atherosclerosis.
复制标题
髓系细胞中丙酮酸激酶M2（PKM2）缺失可增强噬菌作用并减轻动脉粥样硬化。
DOI：
10.1161/circresaha.121.320704
复制
发表时间：
2022-04-29
影响因子：
20.1
通讯作者：
Chauhan, Anil K.
中科院分区：
文献类型：
--
作者：
Doddapattar, Prakash;Dev, Rishabh;Ghatge, Madankumar;Patel, Rakesh B.;Jain, Manish;Dhanesha, Nirav;Lentz, Steven R.;Chauhan, Anil K.
动脉粥样硬化性冠状动脉疾病患者单核/巨噬细胞中糖酵解酶-丙酮酸激酶-2(PKM2)表达上调。然而，细胞类型特异的PKM2在动脉粥样硬化形成中的作用仍有待确定。我们确定了髓系细胞特异性PKM2是否调节胞吐和动脉粥样硬化。我们在Ldlr缺乏的背景下获得了髓系细胞特异性的PKM2−/−小鼠(PKM2mye-Koldlr−/−)。对照组为产仔鼠PKM2WTLdlr−/−。在雄性和雌性小鼠的整个主动脉和主动脉窦横截面中评估了动脉粥样硬化的易感性，这些小鼠喂食高脂肪“西方”食物14周，从8周开始。与食物饮食相比，喂食高脂肪“西方”饮食的LDLR−/−小鼠的巨噬细胞中PKM2表达上调。尽管胆固醇和甘油三酯水平较高，但髓系细胞特异性PKM2的缺失导致整个主动脉和主动脉窦的病变显着减少。此外，我们还发现，髓系细胞特异性PKM2−/−小鼠皮损中巨噬细胞含量减少与血浆中单核细胞趋化蛋白-1水平降低、巨噬细胞对单核细胞趋化蛋白-1反应的移行减少以及糖酵解率降低有关。从给予西方饮食的髓系特异性PKM2−/−小鼠分离的巨噬细胞显示，包括单核细胞趋化蛋白-1、IL-1β和IL-12在内的促炎基因的表达减少。髓系细胞特异性PKM2−/−小鼠在体外表现出凋亡减少，同时伴随着巨噬细胞吞噬功能的增强和LRP1的上调，在体外和体内的动脉粥样硬化病变中。沉默PKM2缺陷的巨噬细胞中的LRP1可以恢复炎症基因的表达并减少吞噬作用。作为一种治疗干预措施，使用小分子抑制PKM2核转位可以降低LDLR−/−小鼠的糖酵解率，增强胞吐作用，并减轻动脉粥样硬化。髓系细胞中PKM2的基因缺失或限制其核转位可通过抑制炎症和增强胞吐作用来减轻动脉粥样硬化。
The glycolytic enzyme pyruvate kinase muscle 2 (PKM2) is upregulated in monocytes/macrophages of patients with atherosclerotic coronary artery disease. However, the role of cell type-specific PKM2 in the setting of atherosclerosis remains to be defined. We determined whether myeloid cell-specific PKM2 regulates efferocytosis and atherosclerosis. We generated myeloid cell-specific PKM2−/− mice on Ldlr-deficient background (PKM2mye-KOLdlr−/−). Controls were littermate PKM2WTLdlr−/− mice. Susceptibility to atherosclerosis was evaluated in whole aortae and cross sections of the aortic sinus in male and female mice fed a high fat “Western” diet for 14 weeks, starting at eight weeks. PKM2 was upregulated in macrophages of Ldlr−/− mice fed a high-fat “Western” diet compared with chow diet. Myeloid cell-specific deletion of PKM2 led to a significant reduction in lesions in the whole aorta and aortic sinus despite high cholesterol and triglyceride levels. Furthermore, we found decreased macrophage content in the lesions of myeloid cell-specific PKM2−/− mice associated with decreased MCP-1 levels in plasma, reduced transmigration of macrophages in response to MCP-1, and impaired glycolytic rate. Macrophages isolated from myeloid-specific PKM2−/− mice fed the Western diet exhibited reduced expression of pro-inflammatory genes, including MCP-1, IL-1β, and IL-12. Myeloid cell-specific PKM2−/− mice exhibited reduced apoptosis concomitant with enhanced macrophage efferocytosis and upregulation of LRP1 in macrophages in vitro and atherosclerotic lesions in vivo. Silencing LRP1 in PKM2-deficient macrophages restored inflammatory gene expression and reduced efferocytosis. As a therapeutic intervention, inhibiting PKM2 nuclear translocation using a small molecule reduced glycolytic rate, enhanced efferocytosis, and reduced atherosclerosis in Ldlr−/− mice. Genetic deletion of PKM2 in myeloid cells or limiting its nuclear translocation reduces atherosclerosis by suppressing inflammation and enhancing efferocytosis.