Biol. Pharm. Bull. 30(1) 121—127 (2007)

erosclerotic lesions. VSMC proliferation induced by growth factors, such as platelet-derived growth factor (PDGF), is known to be a prerequisite of the intimal thickening that is observed after angioplasty, and mitogen-activated protein kinases (MAPKs) are considered to be a critical step in the proliferation of VSMCs. Pyles et al. reported that MAPKs are activated in response to balloon stretch injury in porcine carotid arteries. Moreover, it has been demonstrated using a carotid artery balloon injury model that MAPK signaling, particularly ERK1/2 signaling, is increased and that medial cell replication following injury is reduced by PD098059. The Akt, a serine/threonine kinase is another important pathway triggered by growth factors, and the activity of Akt has been shown to be stimulated by growth factors acting through receptor tyrosine kinases such as PDGF, epidermal growth factor (EGF), and insulin receptors, and the activation of Akt/PKB by these growth factors has been shown to be mediated by PI3K. The signaling pathway from PI3K to Akt/protein kinase B (PKB) was implicated in some cellular responses of PI3K including protection from apoptosis. Activation of MAPKs transiently stimulates c-fos mRNA expression, which is responsible for the increased VSMC proliferation associated with the development of atherosclerotic disease. AP-1, a transcriptional factor is also required for cell proliferation and tumor progression, and it is also known to regulate the c-fos mRNA expression. After vascular injury, VSMCs are stimulated to divide in response to mitogens, and that they exit G1 and enter the S phase. Recent studies have implicated p27 and p21 as inhibitors of cell-cycle progression by associating them with the growth inhibitory effects of antiproliferative agents. Cyclin-dependent kinase inhibitors (CKIs), such as p27 and p21, inactivate cyclin-CDK complexes in the G1 phase, and are upregulated during arterial repair whereupon they negatively regulate VSMC growth. Compounds with a 1,4-naphthoquinone backbone have many biological and pharmacological effects, i.e., antiviral, antifungal, anticancer, and antiplatelet activities. In previous study, we reported that NQ304, a newly synthesized 1,4-naphthoquinone derivative, has potent antithrombotic effect in mice in vivo, and antiplatelet activities in vitro and ex vivo. However, a synthetic 1,4-naphthoquinone analogue, 2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone, was reported to potently inhibit tumor cell growth and to arrest cell cycle progression at G1 and G2/M. 24) Therefore, we sought to determine whether NQ304 can also suppress VSMC proliferation. In this study, we provide evidences that NQ304 potently inhibits VSMC proliferation and that it inhibits the ERK1/2 and PI3K/Akt signaling pathways in VSMCs. Our results reveal that NQ304 is a potential agent for the treatment of vascular disorders like atherosclerosis.