title: 5,8-Dimethoxy-2-Nonylamino-Naphthalene-1,4-Dione Inhibits Vascular Smooth Muscle Cell Proliferation by Blocking Autophosphorylation of PDGF-Receptor β.
abstract: As the abnormal proliferation of vascular smooth muscle cells (VSMCs) plays a critical role in the development of atherosclerosis and vascular restenosis, a candidate drug with antiproliferative properties is needed. We investigated the antiproliferative action and underlying mechanism of a newly synthesized naphthoquinone derivative, 5,8-dimethoxy-2-nonylamino-naphthalene-1,4-dione (2-nonylamino-DMNQ), using VSMCs treated with platelet-derived growth factor (PDGF). 2-Nonylamino-DMNQ inhibited proliferation and cell number of VSMCs induced by PDGF, but not epidermal growth factor (EGF), in a concentration-dependent manner without any cytotoxicity. This derivative suppressed PDGF-induced [(3)H]-thymidine incorporation, cell cycle progression from G0/G1 to S phase, and the phosphorylation of phosphor-retinoblastoma protein (pRb) as well as the expression of cyclin E/D, cyclin-dependent kinase (CDK) 2/4, and proliferating cell nuclear antigen (PCNA). Importantly, 2-nonylamino-DMNQ inhibited the phosphorylation of PDGF receptorβ(PDGF-Rβ) enhanced by PDGF at Tyr(579), Tyr(716), Tyr(751), and Tyr(1021) residues. Subsequently, 2-nonylamino-DMNQ inhibited PDGF-induced phosphorylation of STAT3, ERK1/2, Akt, and PLCγ1. Therefore, our results indicate that 2-nonylamino-DMNQ inhibits PDGF-induced VSMC proliferation by blocking PDGF-Rβ autophosphorylation, and subsequently PDGF-Rβ-mediated downstream signaling pathways.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Kim
authors.forename: Jung-Jin
authors.initials: JJ
authors.lastname: Lee
authors.forename: Sang-Gil
authors.initials: SG
authors.lastname: Lee
authors.forename: Sang-Hyuk
authors.initials: SH
authors.lastname: Jung
authors.forename: Joo-Hui
authors.initials: JH
authors.lastname: Han
authors.forename: So Young
authors.initials: SY
authors.lastname: Yang
authors.forename: Eunju
authors.initials: E
authors.lastname: Yun
authors.forename: Gyu-Yong
authors.initials: GY
authors.lastname: Song
authors.forename: Chang-Seon
authors.initials: CS
authors.lastname: Myung
keywords: 2-Nonylamino-DMNQ; Cardiovascular diseases; Platelet-derived growth factor receptor-β; Proliferation; Vascular smooth muscle cell