抑制PFKFB3表达刺激急性心肌梗死后巨噬细胞介导的淋巴管生成

Tianyi Cui, Chao Feng, Hantao Jiang, Ying Jin, Jinping Feng
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引用次数: 0

摘要

背景:淋巴管扩张在维持心脏功能中起着至关重要的作用,而淋巴管扩张的缺乏可能导致心力衰竭(HF),并随后导致急性心肌梗死(AMI)。巨噬细胞通过分泌血管内皮细胞生长因子C (VEGF-C)参与诱导淋巴管生成,但其确切机制尚不清楚。方法:在心肌内注射腺相关病毒(AAV9)抑制VEGFR3 (VEGFR3 shRNA)的表达或促进VEGFR3 (VEGFR3 ORF)在心脏中的表达;采用Myh6-mCherry B6 D2-tg小鼠和流式细胞术检测纵隔淋巴结内心肌细胞碎片数量;荧光染色和qPCR评价荧光分析;采用海马实验评价巨噬细胞糖酵解水平;以Lyz2扮成𝑟𝑒、VEGFCfl/fl和PFKFB3fl/fl小鼠为模型敲除巨噬细胞中VEGF-C和PFKFB3的表达。结果:心肌组织中VEGFR3水平升高可促进心肌碎片向纵隔淋巴结引流,从而改善心功能,减少再灌注损伤后的纤维化。相反,髓系VEGF-C缺乏在再灌注损伤后显示巨噬细胞计数和炎症水平增加。抑制巨噬细胞糖酵解关键酶PFKFB3可刺激VEGF-C在巨噬细胞中的表现。髓系PFKFB3缺乏与再灌注损伤后诱导的淋巴管生成有关。结论:我们的初步研究表明,抑制巨噬细胞中PFKFB3的表达可能会刺激这些免疫细胞中VEGF-C的产生,从而促进淋巴管生成,减轻I/R损伤的炎症作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of PFKFB3 Expression Stimulates Macrophage-Mediated Lymphangiogenesis Post-Acute Myocardial Infarction
Background: The dilation of lymphatic vessels plays a critical role in maintaining heart function, while a lack thereof could contribute to heart failure (HF), and subsequently to an acute myocardial infarction (AMI). Macrophages participate in the induction of lymphangiogenesis by secreting vascular endothelial cell growth factor C (VEGF-C), although the precise mechanism remains unclear. Methods: Intramyocardial injections of adeno-associated viruses (AAV9) to inhibit the expression of VEGFR3 (VEGFR3 shRNA) or promote the expression of VEGFR3 (VEGFR3 ORF) in the heart; Myh6-mCherry B6 D2-tg mice and flow cytometry were used to evaluate the number of myocellular debris in the mediastinal lymph nodes; fluorescence staining and qPCR were used to evaluate fluorescence analysis; seahorse experiment was used to evaluate the level of glycolysis of macrophages; Lyz2𝐶𝑟𝑒, VEGFCfl/fl, and PFKFB3fl/fl mice were used as a model to knock out the expression of VEGF-C and PFKFB3 in macrophages. Results: The escalation of VEGFR3 in cardiac tissue can facilitate the drainage of myocardial debris to the mediastinal lymph nodes, thereby improving cardiac function and reducing fibrosis after reperfusion injury. Conversely, myeloid VEGF-C deficiency displayed an increase in macrophage counts and inflammation levels following reperfusion injury. The inhibition of the critical enzyme PFKFB3 in macrophage glycolysis can stimulate the manifestation of VEGF-C in macrophages. A deficiency in myeloid PFKFB3 is associated with induced lymphangiogenesis following reperfusion injury. Conclusions: Our initial investigations suggest that the suppression of PFKFB3 expression in macrophages could potentially stimulate the production of VEGF-C in these immune cells, which in turn may facilitate lymphangiogenesis and mitigate the inflammatory effects of I/R injury.
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