Effect of vectors on human endothelial cell signal transduction: implications for cardiovascular gene therapy.

نویسندگان

  • 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
چکیده

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 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.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

نگاهی به ژن درمانی، پیشرفت‏های اخیر و چشم انداز آینده

Human gene therapy has attracted increasing attention as a highly encouraging therapeutic approach to treat wide variety of diseases, other than genetically inherited and monogenic disorders. This approach entails the introduction and expression of a variety of nucleic acids into human target cells for therapeutic purposes. In this article, we review the history, highlights, recently progresses...

متن کامل

The Canonical Wnt Signaling (Wnt/β-Catenin Pathway): A Potential Target for Cancer Prevention and Therapy

Precise regulation of signal transduction pathways is crucial for normal animal development and for maintaining cellular and tissue homeostasis in adults. The Wnt/Frizzled-mediated signaling includes canonical and non-canonical signal transduction pathways. Upregulation or downregulation of the canonical Wnt-signaling (or the Wnt/β-Catenin signal transduction) leads to a variety of human diseas...

متن کامل

HIV-Derived Lentiviral Vectors: Current Progress toward Gene Therapy and DNA Vaccination

Lentiviral vectors are promising gene delivery tools capable of transducing a variety of dividing and non-dividing cells, including pluripotent stem cells which are refractory for transduction by murine retroviruses. Although there is a growing debate on the safety of lentiviral vectors for gene transfer, in particular for those derived from human immunodeficiency viruses, type one (HIV-1) and ...

متن کامل

Gene Delivery to Mesenchymal Stem Cells

There is increasing trend in using recombinant stem cells as novel therapeutic candidates in different diseases. These studies encompass different applications from targeted homing of Mesenchymal Stromal (stem) Cells (MSC), to arming them with different cytokines. Resistance to transfection or transduction methods had urged researchers to look for better gene delivery alternates and optimizing ...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Arteriosclerosis, thrombosis, and vascular biology

دوره 26 3  شماره 

صفحات  -

تاریخ انتشار 2006