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Cytoskeletal activation and altered gene expression in endothelial barrier regulation by simvastatin.
- Source :
-
American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2004 May; Vol. 30 (5), pp. 662-70. Date of Electronic Publication: 2003 Nov 20. - Publication Year :
- 2004
-
Abstract
- 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 microM, 16 h) demonstrated significant reductions in thrombin-induced (1 U/ml) barrier dysfunction ( approximately 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 microg/ml, 16 h) abolished simvastatin-mediated barrier protection. Robust alterations were noted in the expression of cytoskeletal proteins (caldesmon, integrin beta4), 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.
- Subjects :
- Actins metabolism
Animals
Cells, Cultured
Cortactin
Electrophysiology
Endothelium, Vascular metabolism
Enzyme Activation
Hemostatics pharmacology
Humans
Microfilament Proteins metabolism
Signal Transduction physiology
Thrombin pharmacology
rac GTP-Binding Proteins metabolism
rho GTP-Binding Proteins metabolism
Cytoskeleton metabolism
Endothelial Cells drug effects
Endothelial Cells physiology
Endothelium, Vascular cytology
Gene Expression Regulation drug effects
Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology
Simvastatin pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1044-1549
- Volume :
- 30
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of respiratory cell and molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 14630613
- Full Text :
- https://doi.org/10.1165/rcmb.2003-0267OC