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Akt/FOXO3a signaling modulates the endothelial stress response through regulation of heat shock protein 70 expression
Author(s) -
Kim HyoSoo,
Skurk Carsten,
Maatz Henrike,
Shiojima Ichiro,
Ivashchenko Yuri,
Yoon SukWon,
Park YoungBae,
Walsh Kenneth
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2841fje
Subject(s) - akt1 , protein kinase b , hsp70 , pi3k/akt/mtor pathway , biology , microbiology and biotechnology , signal transduction , umbilical vein , heat shock protein , apoptosis , microarray analysis techniques , endothelial stem cell , gene expression , gene , genetics , in vitro
To identify new antiapoptotic targets of the PI3K‐Akt signaling pathway in endothelial cells, adenovirus‐mediated Akt1 gene transfer and oligonucleotide microarrays were used to examine Akt‐regulated transcripts. DNA microarray analysis revealed that HSP70 expression underwent the greatest fold activation of 12,532 transcripts examined in human umbilical vein endothelial cells (HUVEC) transduced with constitutively active Akt1. Akt1 gene transfer increased HSP70 transcript expression by 24.8‐fold as determined by quantitative PCR and promoted a dose‐dependent up‐regulation of HSP70 protein as determined by Western immunoblot analysis. Gene transfer of FOXO3a, a downstream target of Akt in endothelial cells, significantly suppressed both basal and stress‐induced HSP70 protein expression. FOXO3a induced caspase‐9‐dependent apoptosis in HUVEC, and cotransduction with Ad‐HSP70 rescued endothelial cells from FOXO3a‐induced apoptosis under basal and stress conditions. Our results identify HSP70 as a new antiapoptotic target of Akt‐FOXO3a signaling in endothelial cells that controls viability through modulation of the stress‐induced intrinsic cell death pathway.