Department of Cardiology, First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China.
Department of Oncology, Qingdao Municipal Hospital Group, Qingdao 266000, Shandong Province, China.
Thromb Res. 2021 Jan;197:36-43. doi: 10.1016/j.thromres.2020.10.028. Epub 2020 Nov 1.
Patients with essential hypertension (EH) and hyperhomocysteinemia (HHCY) suffer from more increased thrombotic events than those in EH alone. However, the underlying mechanisms for this effect are not well understood. This study hypothesized that neutrophil extracellular trap (NET) releasing may be triggered by HHCY in patients in EH, thereby predisposing them to a more hypercoagulable state. Using a modified-capture enzyme-linked immunosorbent assay (ELISA) method, we observed that cell-free DNA (CF-DNA) and myeloperoxidase DNA (MPO-DNA) in patients With EH and HHCY were significantly higher. The NET formation was also positively correlated with homocysteine levels, neutrophil-lymphocyte ratio (NLR), and hypercoagulable markers (thrombin-antithrombin complex, D-dimers). Furthermore, neutrophils from patients in EH with HHCY were found to be predisposed to amplified NET release when compared to patients in EH without HHCY or CTR. Coagulation function assays showed that NETs in patients With EH and HHCY resulted in a significantly increased ability to generate thrombin and fibrin than in those in EH without HHCY or CTR. These procoagulant effects of NETs in patients With EH and HHCY were markedly inhibited (approximately 70%) by the cleavage of NETs with DNase I. Isolated NETs from patients With EH and HHCY neutrophils also exerted a strong cytotoxic effect on endothelial cells (ECs), converted them to apoptosis. This study revealed a previously unrecognized association between the hypercoagulable state and neutrophils in patients With EH and HHCY. Therefore, blocking NETs may represent a new therapeutic objective for preventing thrombosis in these patients.
患有原发性高血压（EH）和高同型半胱氨酸血症（HHCY）的患者比单纯 EH 患者发生更多的血栓事件。然而，这种作用的潜在机制尚不清楚。本研究假设 HHCY 可能会在 EH 患者中触发中性粒细胞胞外诱捕网（NET）的释放，从而使他们更容易处于高凝状态。使用改良的捕获酶联免疫吸附测定（ELISA）方法，我们观察到 EH 和 HHCY 患者的无细胞 DNA（CF-DNA）和髓过氧化物酶 DNA（MPO-DNA）明显升高。NET 的形成也与同型半胱氨酸水平、中性粒细胞-淋巴细胞比值（NLR）和高凝标志物（凝血酶-抗凝血酶复合物、D-二聚体）呈正相关。此外，与 EH 无 HHCY 或对照组相比，EH 伴 HHCY 的患者的中性粒细胞更容易发生扩增的 NET 释放。凝血功能检测显示，EH 和 HHCY 患者的 NET 导致生成凝血酶和纤维蛋白的能力明显高于 EH 无 HHCY 或对照组。NET 对凝血的促凝作用在 EH 和 HHCY 患者中被 DNase I 切割显著抑制（约 70%）。来自 EH 和 HHCY 患者中性粒细胞的分离 NET 也对内皮细胞（EC）产生强烈的细胞毒性作用，将其转化为凋亡。这项研究揭示了 EH 和 HHCY 患者高凝状态和中性粒细胞之间以前未被认识到的关联。因此，阻断 NET 可能代表预防这些患者血栓形成的新治疗目标。
