Cytokine Profile in Experimental Models of Critical Limb Ischemia in Rats

Лыков, А. П.; Бондаренко, Н. А.; Повещенко, О. В.; Kabakov, Alexander E.; Суровцева, М. А.; Kim, I. I.; Kazakov, O. V.; Повещенко, А. Ф.; Yankaite, E. V.

doi:10.1007/s10517-019-04666-y

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“…The vascular endothelium responds rapidly to changes in oxygen tension and nutrients (Shweiki et al, 1992). In response to ischemic insult, endothelial cells produce and release cytokines (Lykov et al, 2019) which recruit inflammatory cells to sites of injury. In humans, neutrophils are the most abundant circulating leukocytes with a high rate of production and turnover (Lahoz-Beneytez et al, 2016) and can rapidly respond to the injured endothelium.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil-Derived Myeloperoxidase and Hypochlorous Acid Critically Contribute to 20-Hydroxyeicosatetraenoic Acid Increases that Drive Postischemic Angiogenesis

Azcona

Tang

Berry

et al. 2022

J Pharmacol Exp Ther

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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 LCMS/MS/MS, Laser Doppler Perfusion Imaging (LDPI), and Microvascular Density (MVD) 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 post-ischemia 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 post-ischemic compensatory angiogenesis.

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Section: Introductionmentioning

confidence: 99%