KLF4 regulates FAM3A to promotes angiotensin II-induced proliferation and migration of vascular smooth muscle cells through the PI3K/AKT signaling pathway

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides Pub Date : 2025-02-25 DOI:10.1016/j.peptides.2025.171379

Min Zhang, Rong Lei, Liqiong Wang, Yimin Jiang, Xiaoyan Zhou, Yuquan Wang

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引用次数: 0

Abstract

Background

Hypertension, a major cause of cardiovascular disease, is linked to vascular remodeling, which is influenced by phenotypic changes in vascular smooth muscle cells (VSMCs). Studies have shown that KLF4 influences vascular remodeling by promoting VSMC dedifferentiation, increasing proliferation, and enhancing inflammatory responses, while FAM3 may play a key role in VSMC migration and proliferation. Angiotensin II (Ang II) contributes to remodeling, but the mechanisms are unclear.

Methods

Ang II was used to stimulate VSMCs in order to evaluate the expression levels of KLF4 and FAM3A. EdU assays, transwell and scratch wound healing assays measured proliferation and migration. KLF4 knockdown and overexpression experiments were performed to examine the effects on FAM3A expression and VSMC behavior. Western blotting was conducted to analyze protein expression levels of KLF4, FAM3A, and PI3K/AKT signaling components. Bioinformatics analysis was used to predict KLF4 binding sites on the FAM3A promoter. Luciferase and CHIP assays confirmed regulation.

Results

Ang II stimulation increased VSMC proliferation, migration, and the expression of KLF4 and FAM3A. Knockdown of KLF4 reduced Ang II-induced proliferation and migration of VSMCs, accompanied by decreased FAM3A expression. Conversely, overexpression of KLF4 enhanced FAM3A levels, promoting VSMC proliferation and migration. Bioinformatics, luciferase reporter assays and CHIP assay confirmed that KLF4 directly binds to the FAM3A promoter. FAM3A knockdown inhibited Ang II-induced VSMC proliferation and migration by reducing PI3K/AKT pathway activation, whereas FAM3A overexpression reversed the inhibitory effects of KLF4 knockdown.

Conclusion

KLF4 transcriptionally regulates FAM3A, modulating Ang II-induced VSMC proliferation and migration through the PI3K/AKT signaling pathway.

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KLF4通过PI3K/AKT信号通路调控FAM3A，促进血管紧张素ii诱导的血管平滑肌细胞增殖和迁移。

背景：高血压是心血管疾病的主要原因之一，与血管重构有关，血管重构受血管平滑肌细胞（VSMCs）表型变化的影响。研究表明KLF4通过促进VSMC去分化、增加增殖、增强炎症反应等方式影响血管重构，而FAM3可能在VSMC迁移和增殖中发挥关键作用。血管紧张素II （Ang II）有助于重塑，但机制尚不清楚。方法：采用Angⅱ刺激VSMCs，评价KLF4和FAM3A的表达水平。EdU试验、transwell和划伤愈合试验测量了增殖和迁移。通过KLF4敲低和过表达实验，观察对FAM3A表达和VSMC行为的影响。Western blotting分析KLF4、FAM3A、PI3K/AKT信号组分的蛋白表达水平。利用生物信息学分析预测FAM3A启动子上KLF4的结合位点。荧光素酶和CHIP检测证实有调节作用。结果：Ang II刺激增加VSMC的增殖、迁移和KLF4、FAM3A的表达。敲低KLF4可降低Angⅱ诱导的VSMCs的增殖和迁移，同时降低FAM3A的表达。相反，过表达KLF4可增强FAM3A水平，促进VSMC的增殖和迁移。生物信息学、荧光素酶报告基因检测和CHIP检测证实KLF4直接结合FAM3A启动子。FAM3A敲低通过降低PI3K/AKT通路激活抑制Ang ii诱导的VSMC增殖和迁移，而FAM3A过表达逆转了KLF4敲低的抑制作用。结论：KLF4转录调控FAM3A，通过PI3K/AKT信号通路调节Ang ii诱导的VSMC增殖和迁移。

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

Peptides 医学-生化与分子生物学

CiteScore

6.40

自引率

6.70%

发文量

130

审稿时长

28 days

期刊介绍： Peptides is an international journal presenting original contributions on the biochemistry, physiology and pharmacology of biological active peptides, as well as their functions that relate to gastroenterology, endocrinology, and behavioral effects. Peptides emphasizes all aspects of high profile peptide research in mammals and non-mammalian vertebrates. Special consideration can be given to plants and invertebrates. Submission of articles with clinical relevance is particularly encouraged.