慢性血流紊乱通过 DNA 甲基转移酶依赖性内皮细胞向间质转化诱导表层侵蚀性病变

IF 3 2区 医学 Q2 PERIPHERAL VASCULAR DISEASE
Journal of atherosclerosis and thrombosis Pub Date : 2025-05-01 Epub Date: 2024-11-15 DOI:10.5551/jat.64990
Caiying Tang, Guoxia Shi, Ruyi Jia, Xueying Pei, Chao Wang, Zhuo Du, Song Li, Pingping Wan, Sibo Sun, Cong Peng, Shuang Li, Ping Sun, Bo Yu, Jiannan Dai
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引用次数: 0

摘要

目的:在所有急性冠状动脉综合征(ACS)病例中,浅表侵蚀约占三分之一。此前,我们发现附近的分叉与表层侵蚀有独立关联;然而,长期振荡流动对表层侵蚀的影响仍未得到探讨。内皮细胞向间充质转化(EndMT)是一个动态过程,在这一过程中,内皮细胞获得间充质特性,进而产生平滑肌细胞(SMC)样细胞和细胞外基质(ECM)堆积,这与浅表侵蚀的尸检病理相似。这一发现促使我们怀疑 EndMT 在慢性震荡流对浅表糜烂的影响中起了作用:方法:我们在小鼠颈动脉中建立了摆动流,并在 4 周后分析了新内膜增生、内皮连续性、ECM 含量和 EndMT 标记。此外,还进行了生物信息数据分析和体外研究,以阐明其潜在机制:结果:长期暴露于摆动流的颈动脉表现出增生的新内膜,内皮连续性降低,SMC样细胞和ECM增加,表明浅表易侵蚀病变。此外,摆动流还能显著诱导内膜增生,而抑制内膜增生则能改善浅表易侵蚀病变的形成。生物信息学数据分析和体外研究显示,抗 EndMT 的 KLF2 和 KLF4 以 DNA 甲基转移酶(DNMT)依赖的方式显著减少,抑制 DNMT 可减轻振荡流诱导的 EndMT 和浅表易侵蚀病变:结论:慢性震荡流以 DNMT 依赖性方式激活 EndMT,从而导致浅表易侵蚀病变。我们的研究结果为预防浅表侵蚀提供了一种有前景的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Chronic Disturbed Flow Induces Superficial Erosion-Prone Lesion via Endothelial-to-Mesenchymal Transition in a DNA Methyltransferase-Dependent Manner.

Aim: Superficial erosion accounts for approximately one-third of all cases of acute coronary syndrome (ACS). Previously, we found that a nearby bifurcation is independently associated with superficial erosion; however, the effect of long-term oscillatory flow on superficial erosion remains unexplored. Endothelial-to-mesenchymal transition (EndMT) is a dynamic process in which endothelial cells acquire mesenchymal properties and, in turn, give rise to smooth muscle cell (SMC)-like cells and extracellular matrix (ECM) accumulation, similar to the autopsy pathology of superficial erosion. This finding prompted us to suspect that EndMT plays a role in the effect of chronic oscillatory flow on superficial erosion.

Methods: We established oscillatory flow in mouse carotid arteries and analyzed neointimal hyperplasia, endothelial continuity, ECM content, and EndMT markers 4 weeks later. Furthermore, bioinformatic data analyses and in vitro studies were performed to elucidate the underlying mechanisms.

Results: Carotid arteries exposed to long-term oscillatory flow exhibited hyperplastic neointima, reduced endothelial continuity, and increased SMC-like cells and ECM, indicating superficial erosion-prone lesions. In addition, oscillatory flow significantly induced EndMT, whereas inhibition of EndMT ameliorated the formation of superficial erosion-prone lesions. Bioinformatic data analyses and in vitro studies showed a remarkable reduction in anti-EndMT KLF2 and KLF4 in a DNA methyltransferase (DNMT)-dependent manner, and the suppression of DNMTs attenuated oscillatory flow-induced EndMT and superficial erosion-prone lesions.

Conclusions: Chronic oscillatory flow causes superficial erosion-prone lesions by activating EndMT in a DNMT-dependent manner. Our findings highlight a promising therapeutic strategy for the prevention of superficial erosions.

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来源期刊
CiteScore
6.60
自引率
15.90%
发文量
271
审稿时长
1 months
期刊介绍: JAT publishes articles focused on all aspects of research on atherosclerosis, vascular biology, thrombosis, lipid and metabolism.
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