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.

Abstract

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 anti-proliferative 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 (1-10 microM) for 24 h 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 10 microM, 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 G0/G1 phase arrest in cell cycle progression. However, no evidence of NQ304-induced apoptotic or necrotic cell death was obtained, as determined by flow cytometry 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 (1-10 microM) 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.

• Authors: Tack-Joong Kim, Yeo-Pyo Yun
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 30 Issue 1 Pg. 121-7 (Jan 2007) ISSN: 0918-6158 [Print] Japan
• PMID: 17202671 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimitotic Agents
• Naphthoquinones
• Proto-Oncogene Proteins c-fos
• RNA, Messenger
• Transcription Factor AP-1
• DNA
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• NQ304

Topics

• Animals
• Antimitotic Agents (pharmacology, therapeutic use)
• Aorta (drug effects, metabolism)
• Atherosclerosis (drug therapy, pathology)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• DNA (biosynthesis, drug effects)
• Dose-Response Relationship, Drug
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Muscle, Smooth, Vascular (cytology, drug effects, metabolism)
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Naphthoquinones (pharmacology, therapeutic use)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-fos (metabolism)
• RNA, Messenger (metabolism)
• Rats
• Serum (metabolism)
• Signal Transduction (drug effects)
• Transcription Factor AP-1 (metabolism)