Abstract 5550: Inhibition of Smooth Muscle Cell Proliferation and Balloon Injury-Induced Neointimal Hyperplasia Through Activation of PTEN Expression by HO-3867, A Synthetic Curcuminoid
Background: Vascular smooth muscle cell (VSMC) proliferation is a critical event in the development and progression of vascular diseases. PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor gene that has recently been shown to play a vital role in VSMC proliferation. Particularly, depressed levels of PTEN are associated with VSMC proliferation and restenosis. Hence, PTEN is considered to be a potential therapeutic target to inhibit vascular remodeling leading to restenosis. The goal of this study was to evaluate the efficacy and mechanism of HO-3867, a novel fluorinated diarylidenyl piperidone, in the upregulation of PTEN and inhibition of VSMC proliferation and restenosis.
Methods and Results: Experiments were performed using human aortic smooth muscle cells (SMC), in vitro, and a rat carotid artery balloon injury model, in vivo. HO-3867 significantly inhibited the proliferation of serum-stimulated SMCs in a dose (1–10 μM)- and time (12/24 h)-dependent manner. HO-3867 (10 μM) induced cell-cycle arrest at the G1 phase (72% at 24 h) and apoptosis after 48 h of treatment. HO-3867 significantly increased the phosphorylated as well as total levels of PTEN expression in SMCs. Suppression of PTEN expression by PTEN-siRNA transfection reduced p53 and p21 levels, and increased ERK1/2 phosphorylation, resulting in decreased apoptosis. Conversely, overexpression of PTEN by cDNA transfection activated caspase-3 and increased apoptosis. Furthermore, HO-3867 treatment showed significant downregulation of MMP-2, MMP-9, and NF-κB expression in SMCs. Finally, HO-3867 exhibited a dose-dependent inhibition of neointimal hyperplasia in a rat carotid artery, with activation of PTEN and downregulation of MMP and NF-κB expression.
Conclusions: We have shown for the first time that a synthetic curcuminoid (HO-3867) induces G1 cell-cycle arrest and apoptosis in SMCs, in vitro, and inhibits neointimal formation, in vivo, through induction of PTEN expression. HO-3867 appears to be a potent drug, capable of activating PTEN, which is a key target in the prevention of vascular proliferative disorders such as restenosis.