This Article Full Text Full Text (PDF) All Versions of this Article: 96/9/950    most recent 01.RES.0000165867.95291.7bv1 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 Zhang, F. Articles by Rafii, S. Search for Related Content PubMed PubMed Citation Articles by Zhang, F. Articles by Rafii, S. Related Collections Angiogenesis Cell signalling/signal transduction Gene expression Gene regulation Gene therapy Other Vascular biology

(Circulation Research. 2005;96:950.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Adenovirus Vector E4 Gene Regulates Connexin 40 and 43 Expression in Endothelial Cells via PKA and PI3K Signal Pathways

Fan Zhang, Joseph Cheng, George Lam, David K. Jin, Loïc Vincent, Neil R. Hackett, Shiyang Wang, Lauren M. Young, Barbara Hempstead, Ronald G. Crystal, Shahin Rafii

From the Department of Genetic Medicine (F.Z., J.C., G.L., D.K.J., L.V., L.M.Y., R.G.C., S.R.) and Division of Hematology and Oncology (G.L., S.W., B.H., S.R.), and Belfer Gene Therapy Core Facility of Weill Medical of Cornell University (N.R.H., R.G.C.), New York, NY.

Correspondence to Shahin Rafii, MD, Department of Genetic Medicine and Division of Hematology-Oncology, Weill Medical College of Cornell University, 1300 York Ave, Room D601, New York, NY 10021. E-mail srafii{at}med.cornell.edu

Connexins (Cxs) provide a means for intercellular communication and play important roles in the pathophysiology of vascular cardiac diseases. Infection of endothelial cells (ECs) with first-generation E1/E3-deleted E4⁺ adenovirus (AdE4⁺) selectively modulates the survival and angiogenic potential of ECs by as of yet unrecognized mechanisms. We show here that AdE4⁺ vectors potentiate Cx expression in ECs in vitro and in mouse heart tissue. Infection of ECs with AdE4⁺, but not AdE4^–, resulted in a time- and dose-dependent induction of junctional Cx40 expression and suppression of Cx43 protein and mRNA expression. Treatment of ECs with PKA inhibitor H89 or PI3K inhibitor LY294002 prevented the AdE4⁺-mediated regulation of Cx40 and Cx43 that was associated with diminished AdE4⁺-mediated survival of ECs. Moreover, both PKA activity and cAMP-response element (CRE)-binding activity were enhanced by treatment of ECs with AdE4⁺. However, there is no causal evidence of a cross-talk between the 2 modulatory pathways, PKA and PI3K. Remarkably, Cx40 immunostaining was markedly increased and Cx43 was decreased in the heart tissue of mice treated with intra-tracheal AdE4⁺. Taken together, these results suggest that AdE4⁺ may play an important role in the regulation of Cx expression in ECs, and that these effects are mediated by both the PKA/CREB and PI3K signaling pathways.

Key Words: endothelial cells • connexin • PI3K • PKA • adenovirus

This article has been cited by other articles:

				Z. Wang, T. Mitsui, M. Ishida, and J. Arita Adenovirus vectors differentially modulate proliferation of pituitary lactotrophs in primary culture in a mitogen and infection time-dependent manner J. Endocrinol., July 1, 2008; 198(1): 209 - 217. [Abstract] [Full Text] [PDF]

				G. S. Shapiro, C. Van Peursem, D. A. Ornelles, J. Schaack, and J. DeGregori Recombinant Adenoviral Vectors Can Induce Expression of p73 via the E4-orf6/7 Protein. J. Virol., June 1, 2006; 80(11): 5349 - 5360. [Abstract] [Full Text] [PDF]