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KMID : 0811720130170030203
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Korean Journal of Physiology & Pharmacology
2013 Volume.17 No. 3 p.203 ~ p.208
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5,8-Dimethoxy-2-Nonylamino-Naphthalene-1,4-DioneInhibitsVascular Smooth Muscle Cell Proliferation by Blocking Autophosphorylation of PDGF-Receptor ?
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Kim Yo-Han
Lee Jung-Jin
Lee Sang-Gil
Jung Sang-Hyuk
Han Joo-Hui
Yang So-Young
Yun Eun-Ju
Song Gyu-Yong
Myung Chang-Seon
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Abstract
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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 [3H]-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 receptor?(PDGF-R?) enhanced by PDGF at Tyr579, Tyr716, Tyr751, and Tyr1021 residues. Subsequently, 2-nonylamino-DMNQ inhibited PDGF- induced phosphorylation of STAT3, ERK1/2, Akt, and PLC?1. Therefore, our results indicate that 2-nonylamino-DMNQ inhibits PDGF-induced VSMC proliferation by blocking PDGF-R? autophosp- horylation, and subsequently PDGF-R?-mediated downstream signaling pathways.
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KEYWORD
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2-Nonylamino-DMNQ, Cardiovascular diseases, Platelet-derived growth factor receptor-?, Proliferation, Vascular smooth muscle cell
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