Antiproliferative Activity of Acerogenin C, a Macrocyclicdiarylheptanoid, on PDGF-Induced Human Aortic Smooth Muscle Cells Proliferation

摘要

Platelet-derived growth factor (PDGF)-BB is one of the most potent factors in the development and progression of various vascular disorders, such as atherosclerosis and restenosis. PDGF is a major stimulant for vascular smooth muscle cells (VSMCs) proliferation via the mitogenesis signaling pathway. In the present study, we investigated the effect of acerogenin C, a macrocyclicdiarylhep-tanoid, on PDGF-BB-stimulated human aortic smooth muscle cells (HASMCs) proliferation. Acer-ogenin C significantly inhibited PDGF (20 ng/mL)-BB-induced [3H]-thymidine incorporation into DNA at concentrations of 0.1, 1 and 10 μM without any cytotoxicity. Acerogenin C also blocked PDGF-BB-stimulated phosphorylation of PLCγ1 and Akt but had no effect on extracellular signal-regulated kinase 1/2 (ERK1/2) and PDGF beta-receptor (Rβ) activation. In addition, acerogenin C (0.1 - 10 μM) induced cell-cycle arrest in the G1 phase, which was associated with the down-regulation of cyclins and the up-regulation of p27kip1. These results suggest that acerogenin C blocks PDGF-BB-stimulated HASMCs proliferation via G0/G1 arrest in association with the induction of p27kip1 and the suppression of PLCγ1 and phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathways. Furthermore, acerogenin C may be used for prevention and treatment of atherosclerosis during restenosis after coronary angioplasty.