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Published ahead of print on November 20, 2003, doi:10.1165/rcmb.2003-0267OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 30, pp. 662-670, 2004
© 2004 American Thoracic Society
DOI: 10.1165/rcmb.2003-0267OC

Cytoskeletal Activation and Altered Gene Expression in Endothelial Barrier Regulation by Simvastatin

Jeffrey R. Jacobson, Steven M. Dudek, Konstantin G. Birukov, Shui Q. Ye, Dmitry N. Grigoryev, Reda E. Girgis and Joe G. N. Garcia

Center for Translational Respiratory Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Address correspondence to: Joe G. N. Garcia, M.D., Division of Pulmonary & Critical Care, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: drgarcia{at}jhmi.edu

The statins, a class of HMG-CoA reductase inhibitors, directly affect multiple vascular processes via inhibition of geranylgeranylation, a covalent modification essential for Rho GTPase interaction with cell membrane–bound activators. We explored simvastatin effects on endothelial cell actomyosin contraction, gap formation, and barrier dysfunction produced by the edemagenic agent, thrombin. Human pulmonary artery endothelial cells exposed to prolonged simvastatin treatment (5 µM, 16 h) demonstrated significant reductions in thrombin-induced (1 U/ml) barrier dysfunction (~ 70% inhibition) with accelerated barrier recovery, as measured by transendothelial resistance. Furthermore, simvastatin attenuated basal and thrombin-stimulated (1 U/ml, 5 min) myosin light chain diphosphorylation and stress fiber formation while dramatically increasing peripheral immunostaining of actin and cortactin, an actin-binding protein, in conjunction with increased Rac GTPase activity. As both simvastatin-induced Rac activation and barrier protection were delayed (maximal after 16 h), we assessed the role of gene expression and protein translation in the simvastatin response. Simultaneous treatment with cycloheximide (10 µg/ml, 16 h) abolished simvastatin-mediated barrier protection. Robust alterations were noted in the expression of cytoskeletal proteins (caldesmon, integrin ß4), thrombin regulatory elements (PAR-1, thrombomodulin), and signaling genes (guanine nucleotide exchange factors) in response to simvastatin by microarray analysis. These novel observations have broad clinical implications in numerous vascular pathobiologies characterized by alterations in vascular integrity including inflammation, angiogenesis, and acute lung injury.

Abbreviations: endothelial cell, EC • guanine nucleotide exchange factor, GEF • hepatocyte growth factor, HGF • human pulmonary artery endothelial cells, HPAEC • myosin light chain, MLC • MLC kinase, MLCK • nitric oxide, NO • NO synthase, NOS • sphingosine 1-phosphate, Sph 1-P • transendothelial electrical resistance, TER




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