Potent Inhibition of Serum-Stimulated Responses in Vascular Smooth Muscle Cell Proliferation by 2-Chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone, a Newly Synthesized 1,4-Naphthoquinone Derivative(Pharmacology)

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概要

• 論文の詳細を見る

• Atherosclerosis, a disease of the large arteries, is the primary cause of heart disease and stroke. The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenetic factor of vascular disorders like atherosclerosis and restenosis after angioplasty. In the present study, the possible antiproliferative effect of a synthetic 1,4-naphthoquinone derivative, 2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone (NQ304) was investigated on rat aortic VSMCs. NQ304 was shown to potently inhibit 5% fetal bovine serum (FBS)-induced the growth of VSMCs. Pre-treatment of VSMCs with NQ304 (1-10μM) for 24h resulted in significant cell number decreases, i.e., inhibition percentages were 44.75±10.77, 73.85±6.38 and 89.77±6.52% at NQ304 concentrations of 1, 5 and 10μM, respectively. NQ304 was also found to significantly inhibit 5% FBS-induced DNA synthesis in a concentration-dependent manner. Furthermore, NQ304 elevated p21^<cip1> and p27^<kip1> mRNA levels and caused G_0/G_1 phase arrest in cell cycle progression. However, no evidence of NQ304-induced apoptotic or necrotic cell death was obtained, as determined by flow cytometery analysis and DNA fragmentation assays. To investigate the mechanism underlying the anti-proliferative effect of NQ304, we examined the effects of NQ304 on c-fos mRNA expression, activator protein-1 (AP-1) binding activity and extracellular signal-regulated kinase1/2 (ERK1/2) and Akt activation. Pre-treatment of VSMCs with NQ304 (1-10μM) was found to significantly inhibit the 5% FBS-induced phosphorylations of ERK1/2 and Akt, the activation of AP-1 and the expression of c-fos. These data suggest that the anti-proliferative and cell cycle arresting effects of NQ304 on serum-induced VSMCs may be mediated by AP-1 activation downregulation via the suppression of phosphatidylinositol 3-kinase (PI3K)/Akt and ERK1/2 signaling pathways, and it may contribute to the prevention of atherosclerosis through inhibition of VSMC proliferation.

• 公益社団法人日本薬学会の論文
• 2007-01-01

著者

• Kim Tack-joong

  Div. Of Biological Sci. And Technol. Coll. Of Sci. And Technol. Inst. Of Biomaterials Yonsei Univ.

• KIM Tack-Joong

  Research Center for Bioresource and Health, College of Pharmacy, Chungbuk National University

• YUN Yeo-Pyo

  Research Center for Bioresource and Health, College of Pharmacy, Chungbuk National University

• Kim Tack-joong

  Research Center For Bioresource And Health College Of Pharmacy Chungbuk National University

• Yun Yeo-pyo

  Research Center For Bioresource And Health College Of Pharmacy Chungbuk National University

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