PMID- 15831817 OWN - NLM STAT- MEDLINE DCOM- 20051031 LR - 20231213 IS - 1524-4571 (Electronic) IS - 0009-7330 (Print) IS - 0009-7330 (Linking) VI - 96 IP - 9 DP - 2005 May 13 TI - Adenovirus vector E4 gene regulates connexin 40 and 43 expression in endothelial cells via PKA and PI3K signal pathways. PG - 950-7 AB - 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. FAU - Zhang, Fan AU - Zhang F AD - Department of Genetic Medicine, Belfer Gene Therapy Core Facility of Weill Medical of Cornell University, New York, NY 10021, USA. FAU - Cheng, Joseph AU - Cheng J FAU - Lam, George AU - Lam G FAU - Jin, David K AU - Jin DK FAU - Vincent, Loic AU - Vincent L FAU - Hackett, Neil R AU - Hackett NR FAU - Wang, Shiyang AU - Wang S FAU - Young, Lauren M AU - Young LM FAU - Hempstead, Barbara AU - Hempstead B FAU - Crystal, Ronald G AU - Crystal RG FAU - Rafii, Shahin AU - Rafii S LA - eng GR - P01 HL059312-090006/HL/NHLBI NIH HHS/United States GR - P01 HL067839-020004/HL/NHLBI NIH HHS/United States GR - R01 HL061849-04/HL/NHLBI NIH HHS/United States GR - P01 HL072942-010004/HL/NHLBI NIH HHS/United States GR - R01 HL058707-04/HL/NHLBI NIH HHS/United States GR - HL67839/HL/NHLBI NIH HHS/United States GR - P01 HL067839/HL/NHLBI NIH HHS/United States GR - R01 HL058707-03/HL/NHLBI NIH HHS/United States GR - R01 HL061849-03S1/HL/NHLBI NIH HHS/United States GR - P01 HL059312-060006/HL/NHLBI NIH HHS/United States GR - R01 HL061849-05/HL/NHLBI NIH HHS/United States GR - P01 HL059312-080006/HL/NHLBI NIH HHS/United States GR - R01 HL075234/HL/NHLBI NIH HHS/United States GR - HHMI/Howard Hughes Medical Institute/United States GR - P01 HL067839-040004/HL/NHLBI NIH HHS/United States GR - P01 HL059312-100006/HL/NHLBI NIH HHS/United States GR - P01 HL072942/HL/NHLBI NIH HHS/United States GR - P01 HL059312/HL/NHLBI NIH HHS/United States GR - P01 HL59312/HL/NHLBI NIH HHS/United States GR - R01 HL061849-03/HL/NHLBI NIH HHS/United States GR - R01 HL061849/HL/NHLBI NIH HHS/United States GR - P01 HL067839-050004/HL/NHLBI NIH HHS/United States GR - P01 HL067839-030004/HL/NHLBI NIH HHS/United States GR - P01 HL059312-070006/HL/NHLBI NIH HHS/United States GR - P01 HL067839-010004/HL/NHLBI NIH HHS/United States GR - R01S HL61849/HL/NHLBI NIH HHS/United States GR - HL66592/HL/NHLBI NIH HHS/United States GR - R01 HL075234-01/HL/NHLBI NIH HHS/United States GR - R01 HL061849-02/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. DEP - 20050414 PL - United States TA - Circ Res JT - Circulation research JID - 0047103 RN - 0 (Adenovirus E4 Proteins) RN - 0 (Connexin 43) RN - 0 (Connexins) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (GTP-Binding Protein alpha Subunits) RN - 0 (Proto-Oncogene Proteins) RN - 0 (RNA, Messenger) RN - EC 2.4.2.31 (Pertussis Toxin) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) SB - IM MH - Adenoviridae/*genetics MH - Adenovirus E4 Proteins/*genetics MH - Animals MH - Connexin 43/analysis/genetics/*metabolism MH - Connexins/analysis/*biosynthesis/genetics MH - Cyclic AMP Response Element-Binding Protein/physiology MH - Cyclic AMP-Dependent Protein Kinases/*metabolism/physiology MH - Endothelial Cells/chemistry/enzymology/metabolism MH - Endothelium, Vascular/cytology/enzymology/*metabolism MH - GTP-Binding Protein alpha Subunits/metabolism MH - Gene Expression Regulation MH - Genetic Vectors MH - Humans MH - Mice MH - Myocardium/metabolism MH - Pertussis Toxin/pharmacology MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Protein Serine-Threonine Kinases/metabolism MH - Proto-Oncogene Proteins/metabolism MH - Proto-Oncogene Proteins c-akt MH - RNA, Messenger/metabolism MH - Signal Transduction MH - Gap Junction alpha-5 Protein PMC - PMC2935198 MID - NIHMS231167 EDAT- 2005/04/16 09:00 MHDA- 2005/11/01 09:00 PMCR- 2010/09/07 CRDT- 2005/04/16 09:00 PHST- 2005/04/16 09:00 [pubmed] PHST- 2005/11/01 09:00 [medline] PHST- 2005/04/16 09:00 [entrez] PHST- 2010/09/07 00:00 [pmc-release] AID - 01.RES.0000165867.95291.7b [pii] AID - 10.1161/01.RES.0000165867.95291.7b [doi] PST - ppublish SO - Circ Res. 2005 May 13;96(9):950-7. doi: 10.1161/01.RES.0000165867.95291.7b. Epub 2005 Apr 14.