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
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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