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The Role of Rho-Associated Kinase in Differential Regulation by Statins of Interleukin-1- and Lipopolysaccharide-Mediated Nuclear Factor B Activation and Inducible Nitric-Oxide Synthase Gene Expression in Vascular Smooth Muscle Cells

Departments of Pharmacology (C.-Y.W., Y.-H.C., P.-F.H., K.-H.L., W.-W.L.) and Family Medicine (K.-C.H.), National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan

An optimal level of NO has protective effects in atherosclerosis, whereas large amounts contribute to septic shock. To study how statins, the potent inhibitors of cholesterol synthesis, regulate NO in the vascular wall, we determined their effects on interleukin-1 (IL-1)- and lipopolysaccharide (LPS)-induced NO production in aortic vascular smooth muscle cells (VSMCs). Compared with the large amounts of NO and inducible NO synthase (iNOS) protein expression induced by LPS, the responses of IL-1 were modest. Various statins were found to inhibit LPS-induced iNOS expression and NO production, although they potentiated IL-1 responses. In addition, fluvastatin increased IL-1-induced p65 nuclear translocation and nuclear factor B (NF-B) activity, although it inhibited those induced by LPS. To address the role of small G proteins in statin's actions, farnesyl transferase inhibitors [-hydroxyfarne-sylphosphonic acid and (2S)-2-[[(2S)-2-[(2S,3S)-2-[(2R)-2-amino-3-mercaptopropyl]amino]-3-methylpentyl]oxy]-1-oxo-3-phenylpropyl]amino]-4-(methylsulfonyl)-butanoic acid 1-methylethyl ester (L-744382)], Rac inhibitor (NSC23766), and Rho-associated kinase (ROCK) inhibitor [N-(4-pyridyl)-4-(1-aminoethyl)cyclohexanecarboxamide dihydrochloride (Y-27632)] were used. We found that Y-27632 potentiated IL-1-induced iNOS expression, p65 nuclear translocation, IB kinase (IKK), and NF-B activation, whereas it had minimal effects on LPS-induced responses. In contrast, farnesyl transferase inhibitors blocked iNOS protein expression induced by LPS and IL-1, whereas NSC23766 had no effect. Further studies showed that LPS down-regulated Rho and ROCK activity, whereas IL-1 increased them, suggesting a negative role of Rho and ROCK signaling, which is regulated in contrary manners by IL-1 and LPS, in IKK/NF-B activation. Through abrogating this negative signaling, statins differentially regulate iNOS expression induced by LPS and IL-1 in VSMCs. These differential actions of statins on iNOS gene regulation might provide an additional explanation for the pleiotropic beneficial effects of statins.

Address correspondence to: Dr. Wan-Wan Lin, Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan. E-mail: wwl{at}ha.mc.ntu.edu.tw

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