This Article Full Text Full Text (PDF) All Versions of this Article: 26/3/462    most recent 01.ATV.0000200083.95349.9ev1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tan, P. H. Articles by George, A. J.T. Search for Related Content PubMed PubMed Citation Articles by Tan, P. H. Articles by George, A. J.T.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:462.)
© 2006 American Heart Association, Inc.

Vascular Biology

Effect of Vectors on Human Endothelial Cell Signal Transduction

Implications for Cardiovascular Gene Therapy

Peng H. Tan; Shao-An Xue; Maria Manunta; Sven C. Beutelspacher; Henrieta Fazekasova; A.K.M. Shamsul Alam; Myra O. McClure; Andrew J.T. George

From the Department of Immunology (P.H.T., S.-A.X., S.C.B., 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.

Correspondence to P.H. Tan, Imperial College London, Hammersmith Hospital, Du Cane Rd, London, W12 ONN UK. 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 NFB, 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-/ß 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.

Viral vectors are efficient at transducing ECs. However, they activate the cells, causing an increased expression of adhesion molecules and cytokines. This is caused by stimulation of intracellular signaling pathways. Blocking these pathways, or cytokines that provide autocrine stimulation, can prevent activation after transduction.

Key Words: endothelial cells • gene therapy • nonviral vectors • signal transduction • viral vectors

This article has been cited by other articles:

				P. M. Rogers, N. Mashtalir, M. A. Rathod, O. Dubuisson, Z. Wang, K. Dasuri, S. Babin, A. Gupta, N. Markward, W. T. Cefalu, et al. Metabolically Favorable Remodeling of Human Adipose Tissue by Human Adenovirus Type 36 Diabetes, September 1, 2008; 57(9): 2321 - 2331. [Abstract] [Full Text] [PDF]

				Z. Q. Wang, W. T. Cefalu, X. H. Zhang, Y. Yu, J. Qin, L. Son, P. M. Rogers, N. Mashtalir, J. R. Bordelon, J. Ye, et al. Human Adenovirus Type 36 Enhances Glucose Uptake in Diabetic and Nondiabetic Human Skeletal Muscle Cells Independent of Insulin Signaling Diabetes, July 1, 2008; 57(7): 1805 - 1813. [Abstract] [Full Text] [PDF]