on December 15, 2005
Published online before print December 15, 2005, doi: 10.1161/01.ATV.0000200083.95349.9e
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Submitted on September 20, 2005
Accepted on November 10, 2005
Effect of Vectors on Human Endothelial Cell Signal Transduction. Implications for Cardiovascular Gene Therapy
Peng H. Tan *;
From the Department of Immunology (P.H.T., S.-A.X., M.M., H.F., A.K.M.S.A., A.J.T.G.), Division of Medicine, Imperial College London, Hammersmith Hospital, London, UK.; Jefferiss Research Trust Laboratories (S.C.B., M.O.M.), Wright-Fleming Institute, Division of Medicine, Imperial College London, St Mary’s Hospital, Norfolk Place, London , UK.
* To whom correspondence should be addressed. E-mail: ptan{at}imperial.ac.uk.
Objective--Endothelium is an important target for gene therapy. We have investigated the effect of viral and nonviral vectors on the phenotype and function of endothelial cells (ECs) and developed methods to block any activation caused by these vectors.
Methods and Results--Transduction of ECs with viral vectors, including adenovirus, lentiviruses, and Moloney murine leukemia virus, can induce a pro-inflammatory phenotype. This activation was reduced when nonviral vectors were used. We demonstrate that after transduction there is upregulation of dsRNA-triggered antiviral and PI3K/Akt signaling pathway. Blockade of the NF
B, PI3-K, or PKR signaling pathways all operated to inhibit partially virally induced activation, and inhibition of both PKR and PI3-K pathways totally blocked EC activation. Furthermore, inhibition of IFN-
/
in addition to PI3-K was effective at preventing EC activation.
Conclusions--Viral vectors, although efficient at transducing ECs, result in their activation. Blockade of the signaling pathways involved in viral activation may be used to prevent such activation.
Key words: endothelial cells • gene therapy • nonviral vectors • signal transduction • viral vectors
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