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miR-181b 通过调节 MAP3K3 信号通路来调控血管内皮衰老。

miR-181b regulates vascular endothelial aging by modulating an MAP3K3 signaling pathway.

机构信息

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Department of Cardiology, The Second Xiangya Hospital of Central South University, Changsha, China.

出版信息

FASEB J. 2022 Jun;36(6):e22353. doi: 10.1096/fj.202200046R.

DOI:10.1096/fj.202200046R
PMID:35593587
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9167053/
Abstract

Endothelial cell (EC) aging plays a vital role in the pathogenesis of cardiovascular disease (CVD). MicroRNAs have emerged as crucial regulators of target gene expression by inhibiting mRNA translation and/or promoting mRNA degradation. We identify an aging-related and oxidative stress-responsive microRNA, miR-181b, that inhibits endothelial cell apoptosis and senescence. In gain- or loss-of-function studies, miR-181b regulated the expression of key apoptosis markers (Bcl2, Bax, cleaved-Caspase3) and senescence markers (p16, p21, γH2AX) and the ratio of apoptotic cells (TUNEL-positive) and senescent cells (SA-βgal-positive) in H O -induced ECs. Mechanistically, miR-181b targets MAP3K3 and modulates a MAP3K3/MKK/MAPK signaling pathway. MAP3K3 knockdown recapitulated the phenotype of miR-181b overexpression and miR-181b was dependent on MAP3K3 for regulating EC apoptosis and senescence. In vivo, miR-181b expression showed a negative correlation with increasing age in the mouse aorta. Endothelial-specific deficiency of miR-181a2b2 increased the target MAP3K3, markers of vascular senescence (p16, p21), and DNA double-strand breaks (γH2AX) in the aorta of aged mice. Collectively, this study unveils an important role of miR-181b in regulating vascular endothelial aging via an MAP3K3-MAPK signaling pathway, providing new potential therapeutic targets for antiaging therapy in CVD.

摘要

内皮细胞 (EC) 衰老在心血管疾病 (CVD) 的发病机制中起着至关重要的作用。microRNAs 通过抑制 mRNA 翻译和/或促进 mRNA 降解，成为靶基因表达的关键调节因子。我们发现了一种与衰老相关且对氧化应激有反应的 microRNA，miR-181b，它可以抑制内皮细胞凋亡和衰老。在功能获得或缺失研究中，miR-181b 调节关键凋亡标志物 (Bcl2、Bax、cleaved-Caspase3) 和衰老标志物 (p16、p21、γH2AX) 的表达以及凋亡细胞 (TUNEL 阳性) 和衰老细胞 (SA-βgal 阳性) 的比例在 H2O2 诱导的 EC 中。在机制上，miR-181b 靶向 MAP3K3 并调节 MAP3K3/MKK/MAPK 信号通路。MAP3K3 敲低再现了 miR-181b 过表达的表型，miR-181b 依赖于 MAP3K3 来调节 EC 凋亡和衰老。在体内，miR-181b 的表达与小鼠主动脉中年龄的增加呈负相关。内皮细胞特异性缺乏 miR-181a2b2 增加了老年小鼠主动脉中血管衰老的靶标 MAP3K3、标志物 (p16、p21) 和 DNA 双链断裂 (γH2AX)。总之，这项研究揭示了 miR-181b 通过 MAP3K3-MAPK 信号通路在调节血管内皮衰老中的重要作用，为 CVD 中的抗衰老治疗提供了新的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0936/9167053/d445ac224cd3/nihms-1811929-f0008.jpg
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