Endothelial MerTK impairment accelerates the development of atherosclerosis

IF 11.9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Redox Biology Pub Date : 2025-09-11 DOI:10.1016/j.redox.2025.103861

Shijie Liu , Jingke Yao , Hongye Huang , Xiaoyuan Bai , Jinzi Wu , Oishani Banerjee , Zhicheng Jin , Bingzhong Xue , Hang Shi , Zufeng Ding

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引用次数: 0

Abstract

Rationale

Atherosclerosis is a chronic inflammatory disease primarily affecting large arteries and is the leading cause of cardiovascular disease. MER proto-oncogene tyrosine kinase (MerTK) plays a key role in regulating efferocytosis, a process for the clearance of apoptotic cells. This study investigates the specific contribution of endothelial MerTK to atherosclerosis development.

Methods

Big data analytics, human microarray analyses, proteomics, and a unique mouse model with MerTK deficiency in endothelial cells (MerTK^flox/floxTie2^Cre) were utilized to elucidate the role of endothelial MerTK in atherosclerosis development.

Results

Our big data analytics, encompassing approximately 98,881 cross analyses including 234 analyses for atherosclerosis in the aortic arch, along with human microarray data, reveal that inflammatory responses play a predominant role in atherosclerosis. In vivo, MerTK^flox/floxTie2^Cre mice and the littermate control MerTK^flox/flox mice were used to establish an early stage of atherosclerosis model through a high-fat diet combined with AAV8-PCSK9 treatment. Consistent with big data analytics and human microarray analyses, our proteomics data showed that MerTK^flox/floxTie2^Cre mice demonstrated significantly enhanced proinflammatory signaling, mitochondrial dysfunction, and activated mitogen-activated protein kinase (MAPK) pathway compared to that of MerTK^flox/flox mice. Endothelial MerTK deficiency induces endothelial dysfunction (enhanced endothelial inflammation, mitochondrial dysfunction, and activation of NADPH oxidases and MAPK signaling pathways) and subsequently causes smooth muscle cell (SMC) phenotypic alterations, ultimately promoting atherosclerosis development. The mechanism studies showed that the miR-218–5p/EC^MerTK/MAPK axis may play an important role in endothelial MerTK-mediated atherosclerosis.

Conclusions

Our findings provide strong evidence that endothelial MerTK impairment serves as a novel mechanism in promoting atherosclerosis development.

查看原文本刊更多论文

内皮细胞MerTK损伤加速动脉粥样硬化的发展

动脉粥样硬化是一种主要影响大动脉的慢性炎症性疾病，是心血管疾病的主要原因。MER原癌基因酪氨酸激酶（MerTK）在调节efferocytosis（一种清除凋亡细胞的过程）中起关键作用。本研究探讨了内皮细胞MerTK在动脉粥样硬化发展中的具体作用。方法利用大数据分析、人体微阵列分析、蛋白质组学和内皮细胞MerTK缺乏的小鼠模型（MerTKflox/floxTie2Cre）来阐明内皮细胞MerTK在动脉粥样硬化发展中的作用。我们的大数据分析，包括大约98,881个交叉分析，其中包括234个主动脉弓动脉粥样硬化分析，以及人体微阵列数据，显示炎症反应在动脉粥样硬化中起主导作用。在体内，采用高脂饮食联合AAV8-PCSK9治疗MerTKflox/floxTie2Cre小鼠和同窝对照MerTKflox/flox小鼠建立早期动脉粥样硬化模型。与大数据分析和人体微阵列分析相一致，我们的蛋白质组学数据显示，与MerTKflox/flox小鼠相比，MerTKflox/floxTie2Cre小鼠表现出显著增强的促炎信号、线粒体功能障碍和激活的丝裂原活化蛋白激酶（MAPK）途径。内皮MerTK缺乏导致内皮功能障碍（内皮炎症增强、线粒体功能障碍、NADPH氧化酶和MAPK信号通路激活），随后导致平滑肌细胞（SMC）表型改变，最终促进动脉粥样硬化的发展。机制研究表明，miR-218-5p /ECMerTK/MAPK轴可能在内皮性mertk介导的动脉粥样硬化中发挥重要作用。结论研究结果有力地证明了内皮细胞MerTK损伤是促进动脉粥样硬化发展的新机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-

CiteScore

19.90

自引率

3.50%

发文量

318

审稿时长

25 days

期刊介绍： Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.