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(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

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