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

Overview

MeSH

  • Animals
  • Cyclic AMP Response Element-Binding Protein
  • Endothelial Cells
  • GTP-Binding Protein alpha Subunits
  • Gene Expression Regulation
  • Genetic Vectors
  • Humans
  • Mice
  • Myocardium
  • Pertussis Toxin
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger
  • Signal Transduction

MeSH Major

  • Adenoviridae
  • Adenovirus E4 Proteins
  • Connexin 43
  • Connexins
  • Cyclic AMP-Dependent Protein Kinases
  • Endothelium, Vascular
  • Phosphatidylinositol 3-Kinases

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.

publication date

  • May 13, 2005

has subject area

  • Adenoviridae
  • Adenovirus E4 Proteins
  • Animals
  • Connexin 43
  • Connexins
  • Cyclic AMP Response Element-Binding Protein
  • Cyclic AMP-Dependent Protein Kinases
  • Endothelial Cells
  • Endothelium, Vascular
  • GTP-Binding Protein alpha Subunits
  • Gene Expression Regulation
  • Genetic Vectors
  • Humans
  • Mice
  • Myocardium
  • Pertussis Toxin
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • RNA, Messenger
  • Signal Transduction

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2935198

Digital Object Identifier (DOI)

  • 10.1161/01.RES.0000165867.95291.7b

PubMed ID

  • 15831817

Additional Document Info

start page

  • 950

end page

  • 957

volume

  • 96

number

  • 9