Title | Adenovirus vector E4 gene regulates connexin 40 and 43 expression in endothelial cells via PKA and PI3K signal pathways. |
Publication Type | Journal Article |
Year of Publication | 2005 |
Authors | Zhang F, Cheng J, Lam G, Jin DK, Vincent L, Hackett NR, Wang S, Young LM, Hempstead B, Crystal RG, Rafii S |
Journal | Circ Res |
Volume | 96 |
Issue | 9 |
Pagination | 950-7 |
Date Published | 2005 May 13 |
ISSN | 1524-4571 |
Keywords | Adenoviridae, Adenovirus E4 Proteins, Animals, Connexin 43, Connexins, Cyclic AMP Response Element-Binding Protein, Cyclic AMP-Dependent Protein Kinases, Endothelial Cells, Endothelium, Vascular, Gene Expression Regulation, Genetic Vectors, GTP-Binding Protein alpha Subunits, Humans, Mice, Myocardium, Pertussis Toxin, Phosphatidylinositol 3-Kinases, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, RNA, Messenger, Signal Transduction |
Abstract | 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. |
DOI | 10.1161/01.RES.0000165867.95291.7b |
Alternate Journal | Circ Res |
PubMed ID | 15831817 |
PubMed Central ID | PMC2935198 |
Grant List | P01 HL059312-090006 / HL / NHLBI NIH HHS / United States P01 HL067839-020004 / HL / NHLBI NIH HHS / United States R01 HL061849-04 / HL / NHLBI NIH HHS / United States P01 HL072942-010004 / HL / NHLBI NIH HHS / United States R01 HL058707-04 / HL / NHLBI NIH HHS / United States HL67839 / HL / NHLBI NIH HHS / United States P01 HL067839 / HL / NHLBI NIH HHS / United States R01 HL058707-03 / HL / NHLBI NIH HHS / United States R01 HL061849-03S1 / HL / NHLBI NIH HHS / United States P01 HL059312-060006 / HL / NHLBI NIH HHS / United States R01 HL061849-05 / HL / NHLBI NIH HHS / United States P01 HL059312-080006 / HL / NHLBI NIH HHS / United States R01 HL075234 / HL / NHLBI NIH HHS / United States / HHMI / Howard Hughes Medical Institute / United States P01 HL067839-040004 / HL / NHLBI NIH HHS / United States P01 HL059312-100006 / HL / NHLBI NIH HHS / United States P01 HL072942 / HL / NHLBI NIH HHS / United States P01 HL059312 / HL / NHLBI NIH HHS / United States P01 HL59312 / HL / NHLBI NIH HHS / United States R01 HL061849-03 / HL / NHLBI NIH HHS / United States R01 HL061849 / HL / NHLBI NIH HHS / United States P01 HL067839-050004 / HL / NHLBI NIH HHS / United States P01 HL067839-030004 / HL / NHLBI NIH HHS / United States P01 HL059312-070006 / HL / NHLBI NIH HHS / United States P01 HL067839-010004 / HL / NHLBI NIH HHS / United States R01S HL61849 / HL / NHLBI NIH HHS / United States HL66592 / HL / NHLBI NIH HHS / United States R01 HL075234-01 / HL / NHLBI NIH HHS / United States R01 HL061849-02 / HL / NHLBI NIH HHS / United States |