Inhibition of vascular smooth-muscle cell proliferation and arterial restenosis by HO-3867, a novel synthetic curcuminoid, through up-regulation of PTEN expression

Karuppaiyah Selvendiran, M. Lakshmi Kuppusamy, Anna Bratasz, Liyue Tong, Brian K. Rivera, Cameron Rink, Chandan K. Sen, Tamás Kálai, Kálmán Hideg, Periannan Kuppusamy

Research output: Article

35 Citations (Scopus)

Abstract

Phosphatase and tensin homolog (PTEN), a tumor suppressor gene, has been shown to play a vital role in vascular smooth muscle cell (SMC) proliferation and hence is a potential therapeutic target to inhibit vascular remodeling. The goal of this study was to evaluate the efficacy and mechanism of HO-3867 [((3E,5E)-3,5-bis[(4-fluorophenyl)methylidene]-1-[(1-hydroxy-2,2,5, 5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl]piperidin-4-one)], a new synthetic curcuminoid, in the inhibition of vascular SMC proliferation and restenosis. Experiments were performed using human aortic SMCs and a rat carotid artery balloon injury model. HO-3867 (10 μM) significantly inhibited the proliferation of serum-stimulated SMCs by inducing cell cycle arrest at the G1 phase (72% at 24 h) and apoptosis (at 48 h). HO-3867 significantly increased the phosphorylated and total levels of PTEN in SMCs. Suppression of PTEN expression by PTEN-small interfering RNA transfection reduced p53 and p21 levels and increased extracellular signal-regulated kinase 1/2 phosphorylation, resulting in decreased apoptosis. Conversely, overexpression of PTEN by cDNA transfection activated caspase-3 and increased apoptosis. Furthermore, HO-3867 significantly down-regulated matrix metalloproteinase (MMP)-2, MMP-9, and nuclear factor (NF)-κB expressions in SMCs. Finally, HO-3867 inhibited arterial neointimal hyperplasia through overexpression of PTEN and down-regulation of MMPs and NF-κB proteins. HO-3867 is a potent drug, capable of overexpressing PTEN, which is a key target in the prevention of vascular remodeling, including restenosis.

Original languageEnglish
Pages (from-to)959-966
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume329
Issue number3
DOIs
Publication statusPublished - jún. 1 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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