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RGFP966 inhibits palmitic acid induced VSMCs phenotypic transition by targeting ATGL

Siyi Zhang1, Fangqin Nie1, Youjie Zeng2

  • 1Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha 410013, China.

Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids
|January 30, 2025
PubMed

Insights

RGFP966, an HDAC3 inhibitor, protects against vascular smooth muscle cell (VSMC) transitions by regulating Adipose triglyceride lipase (ATGL). This offers a potential therapeutic strategy for cardiovascular diseases.

Area of Science:

  • Cardiovascular Biology
  • Cellular Mechanisms
  • Pharmacology

Background:

  • Vascular smooth muscle cell (VSMC) phenotypic switching is central to cardiovascular disease pathology.
  • Histone deacetylase 3 (HDAC3) is upregulated in cardiovascular diseases.
  • RGFP966 is a selective HDAC3 inhibitor.

Purpose of the Study:

  • To investigate the effects of RGFP966 on VSMC phenotypic switching.
  • To explore the underlying molecular mechanisms.

Main Methods:

  • Analysis of HDAC3 expression in Gene Expression Omnibus (GEO) datasets.
  • Cellular assays including CCK-8, Edu, and wound healing to assess VSMC proliferation and migration.
  • Investigated the role of Adipose triglyceride lipase (ATGL) and the mTOR pathway.

Main Results:

  • Palmitic acid (PA) induced lipid droplet accumulation, downregulated ATGL, and increased VSMC viability and migration.
  • RGFP966 reversed PA-induced changes in VSMCs.
  • siRNA targeting ATGL exacerbated PA-induced injury, while 3-Methyladenine (3-MA) partially reversed PA-induced ATGL decrease.
  • PA decreased the p-mTOR/mTOR ratio, which rebounded with RGFP966 treatment.

Conclusions:

  • RGFP966 exhibits a protective effect against VSMC phenotypic transitions.
  • This protection is potentially mediated through the regulation of ATGL.
  • HDAC3 inhibition may represent a therapeutic target for cardiovascular diseases involving VSMC dysfunction.
Abstract

Keywords:
ATGLAutophagyPalmitic acidRGFP966VSMCs

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