circSIRT2/miR-542-3p/VASH1 axis regulates endothelial-to-mesenchymal transition (EndMT) in subretinal fibrosis in age-related macular degeneration models.

IF 8 1区 医学 Q1 CELL BIOLOGY
Aging Cell Pub Date : 2025-01-02 DOI:10.1111/acel.14443
Min Zhang, Jiali Wu, Yimin Wang, Yidong Wu, Xiaoling Wan, Mei Jiang, Qiyu Bo, Jieqiong Chen, Xiaodong Sun
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引用次数: 0

Abstract

Neovascular age-related macular degeneration (nAMD), characterized by choroidal neovascularization (CNV), is one of the leading causes of severe visual impairment and irreversible vision loss around the world. Subretinal fibrosis (SRF) contributes to the incomplete response to anti-vascular endothelial growth factor (VEGF) treatment and is one of the main reasons for long-term poor visual outcomes in nAMD. Reducing SRF is urgently needed in the anti-VEGF era. The role of non-coding RNAs has been implicated in CNV; however, their roles in SRF have not been elucidated yet. Herein, we comprehensively investigated circular RNA (circRNA) profiles in the laser-induced mouse SRF model and the transforming growth factor-β (TGF-β) induced human umbilical vein endothelial cell (HUVEC) fibrosis model. A novel circRNA, circSIRT2, was identified, and its function in SRF and endothelial-to-mesenchymal transition (EndMT) regulation was investigated. circSIRT2 was consistently upregulated in fibrotic models in vivo and in vitro. circSIRT2 overexpression downregulated the fibrotic markers and inhibited the proliferation and migration of endothelial cells in vitro. circSIRT2 overexpression in vivo also reduced SRF area in mice. Mechanistically, circSIRT2 functioned by sponging miR-542-3p, which further upregulated the expression of vasohibin-1 (VASH1) and reduced SRF lesion development. Vitreous delivery of miR-542-3p and VASH1 in the mouse SRF model also confirmed the pro-fibrotic function of miR-542-3p and anti-fibrotic function of VASH1, respectively. In conclusion, circSIRT2 inhibited SRF by binding miR-542-3p, which stimulated the VASH1 expression and subsequently suppressed EndMT. The circSIRT2/miR-542-3p/VASH1 axis may serve as a promising therapeutic target for SRF in nAMD.

circSIRT2/miR-542-3p/VASH1轴调节年龄相关性黄斑变性模型中视网膜下纤维化的内皮到间质转化(EndMT)。
以脉络膜新生血管(CNV)为特征的新生血管性年龄相关性黄斑变性(nAMD)是世界范围内严重视力损害和不可逆视力丧失的主要原因之一。视网膜下纤维化(SRF)导致抗血管内皮生长因子(VEGF)治疗反应不完全,是nAMD患者长期视力不良的主要原因之一。在抗vegf时代,迫切需要降低SRF。非编码rna的作用与CNV有关;然而,它们在SRF中的作用尚未阐明。在此,我们全面研究了激光诱导小鼠SRF模型和转化生长因子-β (TGF-β)诱导的人脐静脉内皮细胞(HUVEC)纤维化模型中的环状RNA (circRNA)谱。研究人员发现了一种新的circRNA circSIRT2,并研究了其在SRF和内皮-间质转化(EndMT)调控中的功能。circSIRT2在体内和体外纤维化模型中持续上调。circSIRT2过表达下调纤维化标志物,抑制内皮细胞的增殖和迁移。体内circSIRT2过表达也减少了小鼠的SRF面积。在机制上,circSIRT2通过海绵化miR-542-3p发挥作用,从而进一步上调vasohibin-1 (VASH1)的表达,减少SRF病变的发展。在小鼠SRF模型中通过玻璃体传递miR-542-3p和VASH1也证实了miR-542-3p的促纤维化功能和VASH1的抗纤维化功能。综上所述,circSIRT2通过结合miR-542-3p抑制SRF,从而刺激VASH1的表达,进而抑制EndMT。circSIRT2/miR-542-3p/VASH1轴可能作为nAMD中SRF的有希望的治疗靶点。
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来源期刊
Aging Cell
Aging Cell Biochemistry, Genetics and Molecular Biology-Cell Biology
自引率
2.60%
发文量
212
期刊介绍: Aging Cell is an Open Access journal that focuses on the core aspects of the biology of aging, encompassing the entire spectrum of geroscience. The journal's content is dedicated to publishing research that uncovers the mechanisms behind the aging process and explores the connections between aging and various age-related diseases. This journal aims to provide a comprehensive understanding of the biological underpinnings of aging and its implications for human health. The journal is widely recognized and its content is abstracted and indexed by numerous databases and services, which facilitates its accessibility and impact in the scientific community. These include: Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Academic Search Premier (EBSCO Publishing) Biological Science Database (ProQuest) CAS: Chemical Abstracts Service (ACS) Embase (Elsevier) InfoTrac (GALE Cengage) Ingenta Select ISI Alerting Services Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) Natural Science Collection (ProQuest) PubMed Dietary Supplement Subset (NLM) Science Citation Index Expanded (Clarivate Analytics) SciTech Premium Collection (ProQuest) Web of Science (Clarivate Analytics) Being indexed in these databases ensures that the research published in Aging Cell is discoverable by researchers, clinicians, and other professionals interested in the field of aging and its associated health issues. This broad coverage helps to disseminate the journal's findings and contributes to the advancement of knowledge in geroscience.
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