Tan Peng H, Xue Shao-An, Manunta Maria, Beutelspacher Sven C, Fazekasova Henrieta, Alam A K M Shamsul, McClure Myra O, George Andrew J T
Division of Medicine, Department of Immunology, Imperial College London, Hammersmith Hospital, London, UK.
Arterioscler Thromb Vasc Biol. 2006 Mar;26(3):462-7. doi: 10.1161/01.ATV.0000200083.95349.9e. Epub 2005 Dec 15.
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.
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.
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.
内皮是基因治疗的重要靶点。我们研究了病毒载体和非病毒载体对内皮细胞（ECs）表型和功能的影响，并开发了阻断这些载体引起的任何激活的方法。
用包括腺病毒、慢病毒和莫洛尼鼠白血病病毒在内的病毒载体转导ECs可诱导促炎表型。使用非病毒载体时，这种激活作用会减弱。我们证明转导后dsRNA触发的抗病毒和PI3K/Akt信号通路会上调。阻断NFκB、PI3-K或PKR信号通路均能部分抑制病毒诱导的激活，同时抑制PKR和PI3-K通路则完全阻断EC激活。此外，除PI3-K外，抑制IFN-α/β也能有效防止EC激活。
病毒载体虽能高效转导ECs，但会导致其激活。阻断病毒激活所涉及的信号通路可用于防止这种激活。
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