Hartman Institute for Therapeutic Organ Regeneration

Adenovirus vector E4 gene regulates connexin 40 and 43 expression in endothelial cells via PKA and PI3K signal pathways.

TitleAdenovirus vector E4 gene regulates connexin 40 and 43 expression in endothelial cells via PKA and PI3K signal pathways.
Publication TypeJournal Article
Year of Publication2005
AuthorsZhang F, Cheng J, Lam G, Jin DK, Vincent L, Hackett NR, Wang S, Young LM, Hempstead B, Crystal RG, Rafii S
JournalCirc Res
Volume96
Issue9
Pagination950-7
Date Published2005 May 13
ISSN1524-4571
KeywordsAdenoviridae, 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.

DOI10.1161/01.RES.0000165867.95291.7b
Alternate JournalCirc Res
PubMed ID15831817
PubMed Central IDPMC2935198
Grant ListP01 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

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