[Show abstract][Hide abstract] ABSTRACT: We previously demonstrated statins to enhance cytokine-mediated nitric oxide (NO) synthesis in vascular smooth muscle cells (VSMC). To clarify the mechanism by which this occurs, we evaluated the effects of fluvastatin in lipopolysaccharide (LPS)-stimulated VSMC. NO production induced by LPS was dose-dependently enhanced by fluvastatin, as were iNOS mRNA levels and iNOS protein expression. Exogenous mevalonate and geranylgeranylpyrophosphate (GGPP) dampened the stimulatory effect of fluvastatin. A pull-down assay demonstrated fluvastatin to decrease levels of GTP-bound Rho A. Moreover, a Rho-kinase inhibitor, Y-27632, was observed to enhance LPS-induced NO production. We recently demonstrated that disrupting F-actin formation dramatically potentiates the ability of LPS to induce iNOS mRNA and protein expression. In the present study, staining of F-actin with nitrobenzoxadiazole (NBD)-phallacidin demonstrated that fluvastatin significantly impairs F-actin stress fiber formation. In light of these results, the ability of statins to increase NO production is due, at least in part, to their ability to block the biosynthesis of mevalonate, thereby preventing isoprenoid biosynthesis. This inhibits Rho/Rho-kinase signalling and, in turn, disrupts the actin cytoskeleton. Further analysis of the signalling pathway by which the actin cytoskeleton affects iNOS expression might yield new insight into mechanisms of regulation of NO production.
Biochimica et Biophysica Acta 09/2004; 1689(3):267-72. · 4.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).The editors of the Journal of Cardiovascular Pharmacology and Biochimica et Biophysica Acta have discovered duplication of data in two manuscripts: “Disruption of the actin cytoskeleton up-regulates iNOS expression in vascular smooth muscle cells” (J. Cardiovasc. Pharmacol., 43 (2004) 209–213) and “Statin blocks Rho/Rho-kinase signaling and disrupts the actin cytoskeleton: relationship to enhancement of LPS-mediated nitric oxide synthesis in vascular smooth muscle cells” (Biochim. Biophys. Acta 1689 (2004) 267–272, doi:10.1016/j.bbadis.2004.04.006). We have requested an explanation from the authors, and an acceptable response has not been received. In the interests of scientific integrity, the editors of both journals have elected to retract both articles.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 08/2004;