血管性血友病因子通过形成中性粒细胞胞外诱捕网加重心力衰竭。

Von Willebrand factor exacerbates heart failure through formation of neutrophil extracellular traps.

机构信息

Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China.

Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100013, China.

出版信息

Eur Heart J. 2024 Oct 5;45(37):3853-3867. doi: 10.1093/eurheartj/ehae517.

DOI:10.1093/eurheartj/ehae517

PMID:39165142

Abstract

BACKGROUND AND AIMS

Heart failure (HF) is a leading cause of mortality worldwide and characterized by significant co-morbidities and dismal prognosis. Neutrophil extracellular traps (NETs) aggravate inflammation in various cardiovascular diseases; however, their function and mechanism of action in HF pathogenesis remain underexplored. This study aimed to investigate the involvement of a novel VWF-SLC44A2-NET axis in HF progression.

METHODS

NET levels were examined in patients with HF and mouse models of transverse aortic constriction (TAC) HF. PAD4 knockout mice and NET inhibitors (GSK-484, DNase I, NEi) were used to evaluate the role of NETs in HF. RNA sequencing was used to investigate the downstream mechanisms. Recombinant human ADAMTS13 (rhADAMTS13), ADAMTS13, and SLC44A2 knockouts were used to identify novel upstream factors of NETs.

RESULTS

Elevated NET levels were observed in patients with HF and TAC mouse models of HF. PAD4 knockout and NET inhibitors improved the cardiac function. Mechanistically, NETs induced mitochondrial dysfunction in cardiomyocytes, inhibiting mitochondrial biogenesis via the NE-TLR4-mediated suppression of PGC-1α. Furthermore, VWF/ADAMTS13 regulated NET formation via SLC44A2. Additionally, sacubitril/valsartan amplifies the cardioprotective effects of the VWF-SLC44A2-NET axis blockade.

CONCLUSIONS

This study established the role of a novel VWF-SLC44A2-NET axis in regulating mitochondrial homeostasis and function, leading to cardiac apoptosis and contributing to HF pathogenesis. Targeting this axis may offer a potential therapeutic approach for HF treatment.

摘要

背景和目的

心力衰竭（HF）是全球范围内导致死亡的主要原因，其特征是存在严重的合并症和预后不良。中性粒细胞胞外诱捕网（NETs）可加重多种心血管疾病的炎症；然而，它们在 HF 发病机制中的功能和作用机制仍未得到充分探索。本研究旨在研究一种新的 VWF-SLC44A2-NET 轴在 HF 进展中的作用。

方法

检查 HF 患者和横主动脉缩窄（TAC）HF 小鼠模型中的 NET 水平。使用 PAD4 敲除小鼠和 NET 抑制剂（GSK-484、DNase I、NEi）来评估 NET 在 HF 中的作用。使用 RNA 测序来研究下游机制。使用重组人 ADAMTS13（rhADAMTS13）、ADAMTS13 和 SLC44A2 敲除来鉴定 NET 的新上游因子。

结果

在 HF 患者和 TAC HF 小鼠模型中观察到 NET 水平升高。PAD4 敲除和 NET 抑制剂改善了心脏功能。从机制上讲，NETs 在心肌细胞中诱导线粒体功能障碍，通过 NE-TLR4 介导的 PGC-1α 抑制抑制线粒体生物发生。此外，VWF/ADAMTS13 通过 SLC44A2 调节 NET 形成。此外，沙库比曲缬沙坦增强了 VWF-SLC44A2-NET 轴阻断的心脏保护作用。