RGFP966 inhibits palmitic acid induced VSMCs phenotypic transition by targeting ATGL

IF 3.3 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochimica et biophysica acta. Molecular and cell biology of lipids Pub Date : 2025-01-28 DOI:10.1016/j.bbalip.2025.159597

Siyi Zhang , Fangqin Nie , Youjie Zeng , Zhousheng Yang , Wenmin Song , Xin Yan , Zizhao Tang , Yangxia Fu , Ren Guo

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Abstract

Background

The phenotypic switch of vascular smooth muscle cells (VSMCs) underlies the pathology of many cardiovascular diseases. Histone deacetylase 3 (HDAC3) is reported to upregulate in several cardiovascular diseases. RGFP966 is a highly selective HDAC3 inhibitor. This study aimed to explore the effects of RGFP966 on the phenotypic switch of VSMCs.

Method

First, we conducted an analysis of HDAC3 expression utilizing pertinent Gene Expression Omnibus (GEO) datasets. Then CCK-8, Edu, and wound healing assays were used to explore the effects of RGFP966 on the proliferation and migration of VSMCs and potential mechanisms at the cellular level.

Results

Our results showed that palmitic acid (PA) induced the accumulation of lipid droplets in VSMCs, downregulated Adipose triglyceride lipase (ATGL), and increased VSMC viability and migration, which were significantly reversed by RGFP966. Additionally, siRNA targeting ATGL dramatically enhanced the VSMCs injury induced by PA. The autophagy inhibitor 3-Methyladenine (3-MA) partially reversed the decreased ATGL expression caused by PA. Furthermore, the p-mTOR/mTOR ratio decreased under PA induction and rebounded after administration of RGFP966.

Conclusion

RGFP966 has a protective effect against VSMCs phenotype transitions, potentially related to the regulation of ATGL.

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RGFP966通过靶向ATGL抑制棕榈酸诱导的VSMCs表型转变。

背景：血管平滑肌细胞（VSMCs）的表型开关是许多心血管疾病的病理基础。据报道，组蛋白去乙酰化酶3 （HDAC3）在几种心血管疾病中上调。RGFP966是一种高选择性HDAC3抑制剂。本研究旨在探讨RGFP966对VSMCs表型转换的影响。方法：首先，我们利用相关的Gene expression Omnibus （GEO）数据集分析了HDAC3的表达。通过CCK-8、Edu和创面愈合实验，探讨RGFP966对VSMCs增殖和迁移的影响及其在细胞水平上的可能机制。结果：我们的研究结果表明，棕榈酸（PA）诱导VSMC中脂滴的积累，下调脂肪甘油三酯脂肪酶（ATGL），增加VSMC的活力和迁移，RGFP966显著逆转了这一作用。此外，靶向ATGL的siRNA显著增强了PA诱导的VSMCs损伤。自噬抑制剂3-甲基腺嘌呤（3-MA）部分逆转了PA引起的ATGL表达下降。此外，p-mTOR/mTOR比值在PA诱导下下降，在给予RGFP966后反弹。结论：RGFP966对VSMCs表型转变具有保护作用，可能与ATGL调控有关。

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来源期刊

Biochimica et biophysica acta. Molecular and cell biology of lipids 生物-生化与分子生物学

CiteScore

11.00

自引率

2.10%

发文量

109

审稿时长

53 days

期刊介绍： BBA Molecular and Cell Biology of Lipids publishes papers on original research dealing with novel aspects of molecular genetics related to the lipidome, the biosynthesis of lipids, the role of lipids in cells and whole organisms, the regulation of lipid metabolism and function, and lipidomics in all organisms. Manuscripts should significantly advance the understanding of the molecular mechanisms underlying biological processes in which lipids are involved. Papers detailing novel methodology must report significant biochemical, molecular, or functional insight in the area of lipids.