红细胞吞噬诱导的铁蛋白沉积有助于肺动脉高压中的肺微血管血栓形成和血栓性血管重塑。

IF 5.5 2区 医学 Q1 HEMATOLOGY Journal of Thrombosis and Haemostasis Pub Date : 2024-09-30 DOI:10.1016/j.jtha.2024.09.011
Yao An, Minghui Xu, Meishan Yan, Hongyu Zhang, Caixia Li, Lifeng Wang, Caixu Liu, Haoran Dong, Li Chen, Lixin Zhang, Yingli Chen, Xu Han, Yun Li, Dongsheng Wang, Chunyan Gao
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引用次数: 0

摘要

背景:无论是原发性还是肺动脉高压(PAH)进展的并发症,血栓形成似乎都是这种疾病的一个重要因素。红细胞(RBC)和肺微血管内皮细胞(PMVECs)之间的交叉对话及其在 PAH 中的作用仍未确定:本研究旨在评估缺氧条件下红细胞与肺微血管内皮细胞相互作用在微血管血栓形成和血栓性血管重塑中的作用:我们建立了 RBC 和 PMVEC 的体外缺氧共孵育模型以及缺氧小鼠模型。我们研究了实验性 PAH 的红细胞吞噬功能(EP)、铁蛋白沉积、血栓形成倾向和肺血流动力学:结果:我们发现,在缺氧条件下,PMVEC 中 EP 的增加引发了铁跃迁,增强了促凝活性,并加剧了血管重塑。在慢性缺氧诱导的 PAH 小鼠模型中,EP 诱导的嗜铁细胞增多和 TMEM16F 的上调导致血栓形成和血栓性血管重塑的高度倾向。抑制铁蛋白沉积或沉默 TMEM16F 可缓解高凝表型,逆转右心室收缩压、右心室肥厚指数和肺血管重塑:这些结果说明了 PAH 中 RBC-PMVEC 相互作用的致病性。这些结果说明了 PAH 中 RBC-PMVEC 相互作用的致病性。抑制 EP、铁肽化或 TMEM16F 可能是预防 PAH 发展和血栓并发症的新型治疗靶点。
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Erythrophagocytosis-induced ferroptosis contributes to pulmonary microvascular thrombosis and thrombotic vascular remodeling in pulmonary arterial hypertension.

Background: Whether primary or just as a complication from the progression of pulmonary arterial hypertension (PAH), thrombosis seems to be an important player in this condition. The crosstalk between red blood cells (RBCs) and pulmonary microvascular endothelial cells (PMVECs) and their role in PAH remain undefined.

Objectives: The goals of this study were to assess the role of RBC-PMVEC interaction in microvascular thrombosis and thrombotic vascular remodeling under hypoxic conditions.

Methods: We established an in vitro hypoxic coincubation model of RBC and PMVEC as well as a hypoxic mouse model. We investigated erythrophagocytosis (EP), ferroptosis, thrombosis tendency, and pulmonary hemodynamics in experimental PAH.

Results: Increased EP in PMVEC triggered ferroptosis, enhanced procoagulant activity, and exacerbated vessel remodeling under hypoxic conditions. In the PAH mouse model induced by chronic hypoxia, EP-induced ferroptosis followed by upregulated TMEM16F led to a high tendency of thrombus formation and thrombotic vascular remodeling. Inhibition of ferroptosis or silencing of TMEM16F could alleviate hypercoagulable phenotype, reverse right ventricular systolic pressure, right ventricular hypertrophy index, and remodeling of pulmonary vessels.

Conclusion: These results illustrate the pathogenic RBC-PMVEC interactions in PAH. Inhibition EP, ferroptosis, or TMEM16F could be a novel therapeutic target to prevent PAH development and thrombotic complications.

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来源期刊
Journal of Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis 医学-外周血管病
CiteScore
24.30
自引率
3.80%
发文量
321
审稿时长
1 months
期刊介绍: The Journal of Thrombosis and Haemostasis (JTH) serves as the official journal of the International Society on Thrombosis and Haemostasis. It is dedicated to advancing science related to thrombosis, bleeding disorders, and vascular biology through the dissemination and exchange of information and ideas within the global research community. Types of Publications: The journal publishes a variety of content, including: Original research reports State-of-the-art reviews Brief reports Case reports Invited commentaries on publications in the Journal Forum articles Correspondence Announcements Scope of Contributions: Editors invite contributions from both fundamental and clinical domains. These include: Basic manuscripts on blood coagulation and fibrinolysis Studies on proteins and reactions related to thrombosis and haemostasis Research on blood platelets and their interactions with other biological systems, such as the vessel wall, blood cells, and invading organisms Clinical manuscripts covering various topics including venous thrombosis, arterial disease, hemophilia, bleeding disorders, and platelet diseases Clinical manuscripts may encompass etiology, diagnostics, prognosis, prevention, and treatment strategies.
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