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, Joe G.N. Garcia

Research output: Contribution to journalArticle

125 Scopus citations

Abstract

The statins, a class of HMC-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 celi 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 β4), 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.

Original languageEnglish (US)
Pages (from-to)662-670
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume30
Issue number5
DOIs
StatePublished - May 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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