Journal
CARDIOVASCULAR RESEARCH
Volume 70, Issue 3, Pages 578-588Publisher
OXFORD UNIV PRESS
DOI: 10.1016/j.cardiores.2006.02.008
Keywords
flow; signal transduction; apoptosis; endothelial; integrin
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Background: To investigate how endothelial cells transduce intracellular signals in response to laminar shear stress (SS), we made use of the papilloma virus oncoprotein E6 which interacts with and induces degradation of numerous cellular proteins including p53 and members of the PDZ-domain family. E6 also recognizes paxillin (PX-N), a fundamental component of focal adhesions, interfering with its association to focal adhesion kinase (FAK). Methods and results: Human umbilical vein endothelial cells, expressing E6 or its mutated variant Delta E6(105-110) (Delta E6) which does not inactivate p53, were cultured under static conditions or exposed to a laminar SS of 12 dyn/cm(2) for 16h. In response to SS, cells expressing E6 or Delta E6 failed to synthesise nitric oxide and directionally remodel their cytoskeleton, as indicated by morphology and phalloidin staining of actin microfilaments. Under these conditions, PXN association with FAK, its localization to the plasma membrane, and its phosphorylation on tyrosine-31, which partially encompasses the PX-N/FAK docking site, were severely compromised. These alterations were paralleled by the impairment of important SS-dependent endothelial functions, including nitric oxide production and survival upon serum deprivation. The direct targeting of PXN expression by RNA interference partially reproduced the E6 phenotype, impairing flow-dependent cell orientation and survival but not nitric oxide production. Conclusions: These results provide evidence that papilloma virus E6 protein interferes with the function of the SS-mechanosensor and suggests a potential a role for PXN in this process. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
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