Ling Shuang, Xu Jin-Wen
Institute of Interdisciplinary Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Oxid Med Cell Longev. 2021 Feb 23;2021:6687096. doi: 10.1155/2021/6687096. eCollection 2021.
Heart failure threatens the lives of patients and reduces their quality of life. Heart failure, especially heart failure with preserved ejection fraction, is closely related to systemic and local cardiac persistent chronic low-grade aseptic inflammation, microvascular damage characterized by endothelial dysfunction, oxidative stress, myocardial remodeling, and fibrosis. However, the initiation and development of persistent chronic low-grade aseptic inflammation is unexplored. Oxidative stress-mediated neutrophil extracellular traps (NETs) are the main immune defense mechanism against external bacterial infections. Furthermore, NETs play important roles in noninfectious diseases. After the onset of myocardial infarction, atrial fibrillation, or myocarditis, neutrophils infiltrate the damaged tissue and aggravate inflammation. In tissue injury, damage-related molecular patterns (DAMPs) may induce pattern recognition receptors (PRRs) to cause NETs, but whether NETs are directly involved in the pathogenesis and development of heart failure and the mechanism is still unclear. In this review, we analyzed the markers of heart failure and heart failure-related diseases and comorbidities, such as mitochondrial DNA, high mobility box group box 1, fibronectin extra domain A, and galectin-3, to explore their role in inducing NETs and to investigate the mechanism of PRRs, such as Toll-like receptors, receptor for advanced glycation end products, cGAS-STING, and C-X-C motif chemokine receptor 2, in activating NETosis. Furthermore, we discussed oxidative stress, especially the possibility that imbalance of thiol redox and MPO-derived HOCl promotes the production of 2-chlorofatty acid and induces NETosis, and analyzed the possibility of NETs triggering coronary microvascular thrombosis. In some heart diseases, the deletion or blocking of neutrophil-specific myeloperoxidase and peptidylarginine deiminase 4 has shown effectiveness. According to the results of current pharmacological studies, MPO and PAD4 inhibitors are effective at least for myocardial infarction, atherosclerosis, and certain autoimmune diseases, whose deterioration can lead to heart failure. This is essential for understanding NETosis as a therapeutic factor of heart failure and the related new pathophysiology and therapeutics of heart failure.
心力衰竭威胁着患者的生命并降低其生活质量。心力衰竭，尤其是射血分数保留的心力衰竭，与全身和局部心脏持续性慢性低度无菌性炎症、以内皮功能障碍为特征的微血管损伤、氧化应激、心肌重塑和纤维化密切相关。然而，持续性慢性低度无菌性炎症的起始和发展尚不清楚。氧化应激介导的中性粒细胞胞外陷阱（NETs）是抵御外部细菌感染的主要免疫防御机制。此外，NETs在非感染性疾病中也发挥着重要作用。心肌梗死、心房颤动或心肌炎发作后，中性粒细胞浸润受损组织并加剧炎症。在组织损伤中，损伤相关分子模式（DAMPs）可能诱导模式识别受体（PRRs）产生NETs，但NETs是否直接参与心力衰竭的发病机制和发展及其机制仍不清楚。在这篇综述中，我们分析了心力衰竭及心力衰竭相关疾病和合并症的标志物，如线粒体DNA、高迁移率族蛋白盒1、纤连蛋白额外结构域A和半乳凝素-3，以探讨它们在诱导NETs中的作用，并研究Toll样受体、晚期糖基化终产物受体、cGAS-STING和C-X-C基序趋化因子受体2等PRRs激活NETosis的机制。此外，我们讨论了氧化应激，特别是硫醇氧化还原失衡和髓过氧化物酶衍生的次氯酸促进2-氯脂肪酸产生并诱导NETosis的可能性，并分析了NETs引发冠状动脉微血管血栓形成的可能性。在一些心脏病中，中性粒细胞特异性髓过氧化物酶和肽基精氨酸脱亚氨酶4的缺失或阻断已显示出有效性。根据目前的药理学研究结果，MPO和PAD4抑制剂至少对心肌梗死、动脉粥样硬化和某些自身免疫性疾病有效，这些疾病的恶化可导致心力衰竭。这对于理解NETosis作为心力衰竭的治疗因素以及心力衰竭相关的新病理生理学和治疗方法至关重要。
