help button home button
AJRCMB
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on November 20, 2003, doi:10.1165/rcmb.2003-0267OC
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
2003-0267OCv1
30/5/662    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jacobson, J. R.
Right arrow Articles by Garcia, J. G. N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jacobson, J. R.
Right arrow Articles by Garcia, J. G. N.
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




This article has been cited by other articles:


Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
W. Chen, S. Pendyala, V. Natarajan, J. G. N. Garcia, and J. R. Jacobson
Endothelial cell barrier protection by simvastatin: GTPase regulation and NADPH oxidase inhibition
Am J Physiol Lung Cell Mol Physiol, October 1, 2008; 295(4): L575 - L583.
[Abstract] [Full Text] [PDF]

Home page
 Biophys. JHome page
F. T. Arce, J. L. Whitlock, A. A. Birukova, K. G. Birukov, M. F. Arnsdorf, R. Lal, J. G. N. Garcia, and S. M. Dudek
Regulation of the Micromechanical Properties of Pulmonary Endothelium by S1P and Thrombin: Role of Cortactin
Biophys. J., July 15, 2008; 95(2): 886 - 894.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
C. D. Ochoa, H. Baker, S. Hasak, R. Matyal, A. Salam, C. A. Hales, W. Hancock, and D. A. Quinn
Cyclic Stretch Affects Pulmonary Endothelial Cell Control of Pulmonary Smooth Muscle Cell Growth
Am. J. Respir. Cell Mol. Biol., July 1, 2008; 39(1): 105 - 112.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
P. A. Singleton, R. Salgia, L. Moreno-Vinasco, J. Moitra, S. Sammani, T. Mirzapoiazova, and J. G. N. Garcia
CD44 Regulates Hepatocyte Growth Factor-mediated Vascular Integrity: ROLE OF c-Met, Tiam1/Rac1, DYNAMIN 2, AND CORTACTIN
J. Biol. Chem., October 19, 2007; 282(42): 30643 - 30657.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
A. A. Birukova, E. Alekseeva, A. Mikaelyan, and K. G. Birukov
HGF attenuates thrombin-induced endothelial permeability by Tiam1-mediated activation of the Rac pathway and by Tiam1/Rac-dependent inhibition of the Rho pathway
FASEB J, September 1, 2007; 21(11): 2776 - 2786.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
N. Takeda, M. Kondo, S. Ito, Y. Ito, K. Shimokata, and H. Kume
Role of RhoA Inactivation in Reduced Cell Proliferation of Human Airway Smooth Muscle by Simvastatin
Am. J. Respir. Cell Mol. Biol., December 1, 2006; 35(6): 722 - 729.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
A. B. Moy, K. Blackwell, M. H. Wu, and H. J. Granger
Growth factor- and heparin-dependent regulation of constitutive and agonist-mediated human endothelial barrier function
Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2126 - H2135.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. R. Jacobson, S. M. Dudek, P. A. Singleton, I. A. Kolosova, A. D. Verin, and J. G. N. Garcia
Endothelial cell barrier enhancement by ATP is mediated by the small GTPase Rac and cortactin.
Am J Physiol Lung Cell Mol Physiol, August 1, 2006; 291(2): L289 - L295.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
E. P. van de Visse, M. van der Heijden, J. Verheij, G. P. van Nieuw Amerongen, V. W. M. van Hinsbergh, A. R. J. Girbes, and A. B. J. Groeneveld
Effect of prior statin therapy on capillary permeability in the lungs after cardiac or vascular surgery.
Eur. Respir. J., May 1, 2006; 27(5): 1026 - 1032.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
L. H. Romer, K. G. Birukov, and J. G.N. Garcia
Focal Adhesions: Paradigm for a Signaling Nexus
Circ. Res., March 17, 2006; 98(5): 606 - 616.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
D. S. Wilkes, T. M. Egan, and H. Y. Reynolds
Lung Transplantation: Opportunities for Research and Clinical Advancement
Am. J. Respir. Crit. Care Med., October 15, 2005; 172(8): 944 - 955.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
P. A. Singleton, S. M. Dudek, E. T. Chiang, and J. G. N. Garcia
Regulation of sphingosine 1-phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P1 receptor, PI3 kinase, Tiam1/Rac1, and {alpha}-actinin
FASEB J, October 1, 2005; 19(12): 1646 - 1656.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
J. R. Jacobson, J. W. Barnard, D. N. Grigoryev, S.-F. Ma, R. M. Tuder, and J. G. N. Garcia
Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury
Am J Physiol Lung Cell Mol Physiol, June 1, 2005; 288(6): L1026 - L1032.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. K. Chowdhury, T. Watkins, N. L. Parinandi, B. Saatian, M. E. Kleinberg, P. V. Usatyuk, and V. Natarajan
Src-mediated Tyrosine Phosphorylation of p47phox in Hyperoxia-induced Activation of NADPH Oxidase and Generation of Reactive Oxygen Species in Lung Endothelial Cells
J. Biol. Chem., May 27, 2005; 280(21): 20700 - 20711.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
J. H. Finigan, S. M. Dudek, P. A. Singleton, E. T. Chiang, J. R. Jacobson, S. M. Camp, S. Q. Ye, and J. G. N. Garcia
Activated Protein C Mediates Novel Lung Endothelial Barrier Enhancement: ROLE OF SPHINGOSINE 1-PHOSPHATE RECEPTOR TRANSACTIVATION
J. Biol. Chem., April 29, 2005; 280(17): 17286 - 17293.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
P. N. Kao
Simvastatin Treatment of Pulmonary Hypertension: An Observational Case Series
Chest, April 1, 2005; 127(4): 1446 - 1452.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. B. Fessler, S. K. Young, S. Jeyaseelan, J. G. Lieber, P. G. Arndt, J. A. Nick, and G. S. Worthen
A Role for Hydroxy-Methylglutaryl Coenzyme A Reductase in Pulmonary Inflammation and Host Defense
Am. J. Respir. Crit. Care Med., March 15, 2005; 171(6): 606 - 615.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
K. Kawkitinarong, L. Linz-McGillem, K. G. Birukov, and J. G. N. Garcia
Differential Regulation of Human Lung Epithelial and Endothelial Barrier Function by Thrombin
Am. J. Respir. Cell Mol. Biol., November 1, 2004; 31(5): 517 - 527.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
F. Zheng, Q.-L. Cheng, A.-R. Plati, S. Q. Ye, M. Berho, A. Banerjee, M. Potier, E. A. Jaimes, H. Yu, Y.-F. Guan, et al.
The Glomerulosclerosis of Aging in Females: Contribution of the Proinflammatory Mesangial Cell Phenotype to Macrophage Infiltration
Am. J. Pathol., November 1, 2004; 165(5): 1789 - 1798.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 2004 American Thoracic Society. 		  ATS Best of the Web