title: Effect of vectors on human endothelial cell signal transduction: implications for cardiovascular gene therapy.
abstract: 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.
  
  
  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 NFkappaB, 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-alpha/beta 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.
authors.affiliation: Division of Medicine, Department of Immunology, Imperial College London, Hammersmith Hospital, London, UK. ptan@imperial.ac.uk
authors.forename: Peng H
authors.initials: PH
authors.lastname: Tan
authors.forename: Shao-An
authors.initials: SA
authors.lastname: Xue
authors.forename: Maria
authors.initials: M
authors.lastname: Manunta
authors.forename: Sven C
authors.initials: SC
authors.lastname: Beutelspacher
authors.forename: Henrieta
authors.initials: H
authors.lastname: Fazekasova
authors.forename: A K M Shamsul
authors.initials: AK
authors.lastname: Alam
authors.forename: Myra O
authors.initials: MO
authors.lastname: McClure
authors.forename: Andrew J T
authors.initials: AJ
authors.lastname: George
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D002318:Cardiovascular Diseases / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000276:immunology; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000276:immunology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008979:Moloney murine leukemia virus / Q000235:genetics; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000009:adverse effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012501:Saphenous Vein / Q000166:cytology; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D014161:Transduction, Genetic; D014657:Vasculitis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt