中性粒细胞髓过氧化物酶和次氯酸根共同促成 20-羟二十碳四烯酸增加，从而驱动缺血后血管生成。
Neutrophil-Derived Myeloperoxidase and Hypochlorous Acid Critically Contribute to 20-Hydroxyeicosatetraenoic Acid Increases that Drive Postischemic Angiogenesis.
机构信息
Department of Pharmacology (J.A.A., F.F.Z., M.L.S., A.M.G.), Department of Biochemistry and Molecular Biology (J.A.A., T.M.J., A.M.G.), Department of Pathology (S.T.), and Department of Physiology (E.B.), New York Medical College, Valhalla, New York; Department of Radiology, Weill Cornell Medicine, New York, New York (J.A.A., T.M.J.); Tufts University, Medford, Massachusetts (R.G.); University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.); and Department of Chemistry, Fudan University, Shanghai, PR China (T.Y.).
Department of Pharmacology (J.A.A., F.F.Z., M.L.S., A.M.G.), Department of Biochemistry and Molecular Biology (J.A.A., T.M.J., A.M.G.), Department of Pathology (S.T.), and Department of Physiology (E.B.), New York Medical College, Valhalla, New York; Department of Radiology, Weill Cornell Medicine, New York, New York (J.A.A., T.M.J.); Tufts University, Medford, Massachusetts (R.G.); University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.); and Department of Chemistry, Fudan University, Shanghai, PR China (T.Y.)
出版信息
J Pharmacol Exp Ther. 2022 Jun;381(3):204-216. doi: 10.1124/jpet.121.001036. Epub 2022 Mar 19.
Compensatory angiogenesis is an important adaptation for recovery from critical ischemia. We recently identified 20-hydroxyeicosatetraenoic acid (20-HETE) as a novel contributor of ischemia-induced angiogenesis. However, the precise mechanisms by which ischemia promotes 20-HETE increases that drive angiogenesis are unknown. This study aims to address the hypothesis that inflammatory neutrophil-derived myeloperoxidase (MPO) and hypochlorous acid (HOCl) critically contribute to 20-HETE increases leading to ischemic angiogenesis. Using Liquid Chromatography-Mass Spectrometry/Mass Spectrometry, Laser Doppler Perfusion Imaging, and Microvascular Density analysis, we found that neutrophil depletion and MPO knockout mitigate angiogenesis and 20-HETE production in the gracilis muscles of mice subjected to hindlimb ischemia. Furthermore, we found MPO and HOCl to be elevated in these tissues postischemia as assessed by immunofluorescence microscopy and in vivo live imaging of HOCl. Next, we demonstrated that the additions of either HOCl or an enzymatic system for generating HOCl to endothelial cells increase the expression of CYP4A11 and its product, 20-HETE. Finally, pharmacological interference of hypoxia inducible factor (HIF) signaling results in ablation of HOCl-induced CYP4A11 transcript and significant reductions in CYP4A11 protein. Collectively, we conclude that neutrophil-derived MPO and its product HOCl activate HIF-1 and CYP4A11 leading to increased 20-HETE production that drives postischemic compensatory angiogenesis. SIGNIFICANCE STATEMENT: Traditionally, neutrophil derived MPO and HOCl are exclusively associated in the innate immunity as potent bactericidal/virucidal factors. The present study establishes a novel paradigm by proposing a unique function for MPO/HOCl as signaling agents that drive critical physiological angiogenesis by activating the CYP4A11-20-HETE signaling axis via a HIF-1α-dependent mechanism. The findings from this study potentially identify novel therapeutic targets for the treatment of ischemia and other diseases associated with abnormal angiogenesis.
代偿性血管生成是从严重缺血中恢复的重要适应机制。我们最近发现 20-羟二十碳四烯酸（20-HETE）是一种新的缺血诱导血管生成的贡献者。然而，缺血促进 20-HETE 增加从而驱动血管生成的确切机制尚不清楚。本研究旨在验证以下假设：炎症中性粒细胞衍生的髓过氧化物酶（MPO）和次氯酸（HOCl）对导致缺血性血管生成的 20-HETE 增加至关重要。通过液相色谱-质谱/质谱、激光多普勒灌注成像和微血管密度分析，我们发现，在接受后肢缺血的小鼠的比目鱼肌中，中性粒细胞耗竭和 MPO 敲除减轻了血管生成和 20-HETE 的产生。此外，我们发现，在这些组织中，免疫荧光显微镜和 HOCl 的体内活体成像评估表明，缺血后 MPO 和 HOCl 升高。接下来，我们证明向内皮细胞中添加 HOCl 或产生 HOCl 的酶系统会增加 CYP4A11 的表达及其产物 20-HETE。最后，缺氧诱导因子（HIF）信号转导的药理学干扰导致 HOCl 诱导的 CYP4A11 转录物的消融和 CYP4A11 蛋白的显著减少。总之，我们得出结论，中性粒细胞衍生的 MPO 及其产物 HOCl 激活 HIF-1 和 CYP4A11，导致增加的 20-HETE 产生，从而驱动缺血后的代偿性血管生成。意义陈述：传统上，中性粒细胞衍生的 MPO 和 HOCl 仅在先天免疫中作为有效的杀菌/抗病毒因子而存在。本研究通过提出一种独特的功能，即 MPO/HOCl 作为信号分子，通过激活 HIF-1α 依赖性机制，通过 CYP4A11-20-HETE 信号轴驱动关键的生理血管生成，为 MPO/HOCl 建立了一个新的范例。这项研究的结果可能为缺血和其他与异常血管生成相关的疾病的治疗确定新的治疗靶点。
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