Research Center, Montreal Heart Institute, Université de Montréal, 5000 Belanger Street, Montreal, QC, H1T 1C8, Canada.
Department of Pharmacology and Physiology , Université de Montréal, Montreal, QC, Canada.
BMC Immunol. 2021 Aug 3;22(1):51. doi: 10.1186/s12865-021-00442-8.
Neutrophils induce the synthesis and release of angiopoietin 1 (Ang1), a cytosolic growth factor involved in angiogenesis and capable of inducing several pro-inflammatory activities in neutrophils. Neutrophils also synthesize and release neutrophil extracellular traps (NETs), comprised from decondensed nuclear DNA filaments carrying proteins such as neutrophil elastase (NE), myeloperoxidase (MPO), proteinase 3 (PR3) and calprotectin (S100A8/S100A9), which together, contribute to the innate immune response against pathogens (e.g., bacteria). NETs are involved in various pathological conditions through pro-inflammatory, pro-thrombotic and endothelial dysfunction effects and have recently been found in heart failure (HF) and type 2 diabetes (T2DM) patients. The aim of the present study was to investigate the role of NETs on the synthesis and release of Ang1 by the neutrophils in patients with T2DM and HF with preserved ejection fraction (HFpEF) (stable or acute decompensated; ADHFpEF) with or without T2DM.
Our data show that at basal level (PBS) and upon treatment with LPS, levels of NETs are slightly increased in patients suffering from T2DM, HFpEF ± T2DM and ADHF without (w/o) T2DM, whereas this increase was significant in ADHFpEF + T2DM patients compared to healthy control (HC) volunteers and ADHFpEF w/o T2DM. We also observed that treatments with PMA or A23187 increase the synthesis of Ang1 (from 150 to 250%) in HC and this effect is amplified in T2DM and in all cohorts of HF patients. Ang1 is completely released (100%) by neutrophils of all groups and does not bind to NETs as opposed to calprotectin.
Our study suggests that severely ill patients with HFpEF and diabetes synthesize and release a greater abundance of NETs while Ang1 exocytosis is independent of NETs synthesis.
中性粒细胞诱导血管生成素 1（Ang1）的合成和释放，Ang1 是一种细胞溶质生长因子，参与血管生成，并能够诱导中性粒细胞中的几种促炎活性。中性粒细胞还合成和释放中性粒细胞胞外诱捕网（NETs），由去凝聚的核 DNA 丝组成，携带中性粒细胞弹性蛋白酶（NE）、髓过氧化物酶（MPO）、蛋白酶 3（PR3）和钙卫蛋白（S100A8/S100A9）等蛋白，共同参与针对病原体（如细菌）的固有免疫反应。NETs 通过促炎、促血栓形成和血管内皮功能障碍等作用参与各种病理状况，并且最近在心力衰竭（HF）和 2 型糖尿病（T2DM）患者中被发现。本研究旨在探讨 NETs 在 T2DM 和射血分数保留的心力衰竭（HFpEF）（稳定或急性失代偿；ADHFpEF）患者中性粒细胞中 Ang1 合成和释放中的作用，无论是否存在 T2DM。
我们的数据表明，在基础水平（PBS）和用 LPS 处理时，患有 T2DM、HFpEF±T2DM 和 ADHF 但无 T2DM 的患者中，NETs 的水平略有增加，而在 ADHFpEF+T2DM 患者中，与健康对照（HC）志愿者和 ADHFpEF 无 T2DM 相比，这种增加是显著的。我们还观察到，用 PMA 或 A23187 处理会增加 HC 中 Ang1 的合成（从 150%增加到 250%），而这种效应在 T2DM 和所有 HF 患者队列中都被放大。Ang1 被所有组的中性粒细胞完全释放（100%），并且与钙卫蛋白不同，不与 NETs 结合。
我们的研究表明，患有严重 HFpEF 和糖尿病的患者合成和释放更多的 NETs，而 Ang1 的胞吐作用不依赖于 NETs 的合成。
