Endothelial cell barrier protection by simvastatin

GTPase regulation and NADPH oxidase inhibition

Weiguo Chen, Srikanth Pendyala, Viswanathan Natarajan, Joe GN Garcia, Jeffrey R. Jacobson

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

The statins, hydroxy-3-methylglutaryl-CoA reductase inhibitors that lower serum cholesterol, exhibit myriad clinical benefits, including enhanced vascular integrity. One potential mechanism underlying increased endothelial cell (EC) barrier function is inhibition of geranylgeranylation, a covalent modification enabling translocation of the small GTPases Rho and Rac to the cell membrane. While RhoA inhibition attenuates actin stress fiber formation and promotes EC barrier function, Rac1 inhibition at the cell membrane potentially prevents activation of NADPH oxidase and subsequent generation of superoxides known to induce barrier disruption. We examined the relative regulatory effects of simvastatin on RhoA, Rac1, and NADPH oxidase activities in the context of human pulmonary artery EC barrier protection. Confluent EC treated with simvastatin demonstrated significantly decreased thrombin-induced FITC-dextran permeability, a reflection of vascular integrity, which was linked temporally to simvastatin-mediated actin cytoskeletal rearrangement. Compared with Rho inhibition alone (Y-27632), simvastatin afforded additional protection against thrombin-mediated barrier dysfunction and attenuated LPS-induced EC permeability and superoxide generation. Statin-mediated inhibition of both Rac translocation to the cell membrane and superoxide production were attenuated by geranylgeranyl pyrophosphate (GGPP), indicating that these effects are due to geranylgeranylation inhibition. Finally, thrombin-induced EC permeability was modestly attenuated by reduced Rac1 expression (small interfering RNA), whereas these effects were made more pronounced by simvastatin pretreatment. Together, these data suggest EC barrier protection by simvastatin is due to dual inhibitory effects on RhoA and Rac1 as well as the attenuation of superoxide generation by EC NADPH oxidase and contribute to the molecular mechanistic understanding of the modulation of EC barrier properties by simvastatin.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume295
Issue number4
DOIs
StatePublished - Oct 2008
Externally publishedYes

Fingerprint

Simvastatin
Cytoprotection
NADPH Oxidase
GTP Phosphohydrolases
Endothelial Cells
Superoxides
Thrombin
Prenylation
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Permeability
Cell Membrane
Blood Vessels
Actins
Stress Fibers
Monomeric GTP-Binding Proteins
Coenzyme A
Small Interfering RNA
Pulmonary Artery
Oxidoreductases
Cholesterol

Keywords

  • Cytoskeleton
  • Permeability
  • Rac
  • Rho
  • Statins

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

Cite this

Endothelial cell barrier protection by simvastatin : GTPase regulation and NADPH oxidase inhibition. / Chen, Weiguo; Pendyala, Srikanth; Natarajan, Viswanathan; Garcia, Joe GN; Jacobson, Jeffrey R.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 295, No. 4, 10.2008.

Research output: Contribution to journalArticle

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