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Published ahead of print on November 20, 2003, doi:10.1165/rcmb.2003-0267OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 5, May 2004, 662-670

A more recent version of this article appeared on May 1, 2004
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Submitted on July 18, 2003
Revised on November 20, 2003

Cytoskeletal activation and altered gene expression in endothelial barrier regulation by simvastatin

Jeffrey R Jacobson1, Steven M Dudek1, Konstantin G Birukov1, Shui Q Ye1, Dmitry N Grigoryev1, Reda E Girgis1, and Joe G Garcia1*

1 Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States

* To whom correspondence should be addressed. 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 (EC) actomyosin contraction, gap formation, and barrier dysfunction produced by the edemagenic agent, thrombin. Human pulmonary artery EC (HPAEC) 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 and as measured by transendothelial resistance (TER). Furthermore, simvastatin attenuated basal and thrombin-stimulated (1 U/ml, 5 min) myosin light chain (MLC) 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, and robust alterations in the expression of cytoskeletal proteins (caldesmon, integrin {beta}4), thrombin regulatory elements (PAR-1, thrombomodulin), and signaling genes (GEFs) were noted 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.




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