FPR2激动作用通过ELOVL6减轻内膜增生减轻再狭窄

IF 4.2 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Qian Zhang, Yuqin Zha, Xiaoting Wang, Peishen Zhao, Owen L. Woodman, Mi Zhou, Yuguo Chen, Xiaojun Zhou, Cheng Xue Qin
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引用次数: 0

摘要

下肢动脉疾病血管内介入治疗后的再狭窄导致了显著的发病率和死亡率。本研究探讨甲酰肽受体2 (FPR2)在新生内膜增生中的作用,并评估选择性FPR2激动剂BMS-986235在减轻再狭窄方面的治疗潜力。与健康对照组相比,再狭窄男性截肢者腘动脉和胫骨前动脉中FPR2的表达显著降低。在内皮损伤后,全身和骨髓特异性FPR2敲除小鼠一致表现出过度的新内膜增生,并伴有血管管腔直径的显着减少。BMS-986235治疗有效地减缓了再狭窄的进展。在机制上,FPR2的激活维持了血管平滑肌细胞(VSMCs)的分化状态,限制了M2巨噬细胞的过度积累,从而限制了新生内膜的重塑。转录组学分析还发现ELOVL脂肪酸延长酶6 (ELOVL6)是FPR2激活的一个新的下游靶点,在再狭窄模型中上调。值得注意的是,BMS-986235降低了巨噬细胞和VSMC中ELOVL6的表达,抑制了VSMC的增殖,减轻了新生内膜增生。FPR2激活通过FPR2/ELOVL6轴维持VSMC分化,从而减轻再狭窄进展,突出其作为预防再狭窄的新治疗靶点的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

FPR2 Agonism Attenuates Restenosis by Mitigating Neointimal Hyperplasia via ELOVL6

FPR2 Agonism Attenuates Restenosis by Mitigating Neointimal Hyperplasia via ELOVL6

FPR2 Agonism Attenuates Restenosis by Mitigating Neointimal Hyperplasia via ELOVL6

FPR2 Agonism Attenuates Restenosis by Mitigating Neointimal Hyperplasia via ELOVL6

Restenosis following endovascular intervention in lower extremity arterial disease contributes to significant morbidity and mortality. This study investigates the role of formylpeptide receptor 2 (FPR2) in neointimal hyperplasia and evaluates the therapeutic potential of the selective FPR2 agonist BMS-986235 in mitigating restenosis. FPR2 expression was significantly reduced in the popliteal and anterior tibial arteries of male amputees with restenosis compared to healthy controls. Whole-body and myeloid-specific FPR2 knockout mice consistently displayed exaggerated neointimal hyperplasia, accompanied by a marked reduction in vessel lumen diameter, following endothelial injury. Treatment with BMS-986235 effectively slowed the progression of restenosis. Mechanistically, FPR2 activation maintained the differentiated state of vascular smooth muscle cells (VSMCs) and limited excessive M2 macrophages accumulation, thereby limiting neointimal remodeling. Transcriptomic analysis additionally identified ELOVL fatty acid elongase 6 (ELOVL6) as a novel downstream target of FPR2 activation, which was upregulated in restenosis models. Notably, BMS-986235 reduced ELOVL6 expression in both macrophages and VSMCs, inhibiting VSMC proliferation and mitigating neointimal hyperplasia. FPR2 activation mitigates restenosis progression by preserving VSMC differentiation through the FPR2/ELOVL6 axis, highlighting its potential as a novel therapeutic target for prevention of restenosis.

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来源期刊
The FASEB Journal
The FASEB Journal 生物-生化与分子生物学
CiteScore
9.20
自引率
2.10%
发文量
6243
审稿时长
3 months
期刊介绍: The FASEB Journal publishes international, transdisciplinary research covering all fields of biology at every level of organization: atomic, molecular, cell, tissue, organ, organismic and population. While the journal strives to include research that cuts across the biological sciences, it also considers submissions that lie within one field, but may have implications for other fields as well. The journal seeks to publish basic and translational research, but also welcomes reports of pre-clinical and early clinical research. In addition to research, review, and hypothesis submissions, The FASEB Journal also seeks perspectives, commentaries, book reviews, and similar content related to the life sciences in its Up Front section.
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