Abstract:
:Mechanisms that preserve endothelial cell (EC) integrity remain elusive, but are critical for new strategies directed against endocrine disorders such as diabetes mellitus (DM). Here we demonstrate in primary cerebral ECs with a clinically relevant model of elevated d-glucose that Akt1 and the post-translational modification and subcellular trafficking of the forkhead transcription factor FoxO3a are critical for early apoptotic membrane signaling and subsequent degradation of nuclear DNA. FoxO3a also directly governs apoptotic mitochondrial signal transduction pathways, since gene knockdown of FoxO3a prevents mitochondrial membrane depolarization as well as the release of cytochrome c. Control of this apoptotic cascade extends to the rapid and progressive activation of caspases. The presence of FoxO3a is necessary for cleaved (active) caspase 1 and 3 expression, since loss of FoxO3a abrogates the induction of caspase activity. Our work identifies Akt1, FoxO3a and closely aligned pathways as key therapeutic targets during impaired glucose tolerance and DM.
journal_name
Mol Cell Endocrinoljournal_title
Molecular and cellular endocrinologyauthors
Hou J,Chong ZZ,Shang YC,Maiese Kdoi
10.1016/j.mce.2010.02.037subject
Has Abstractpub_date
2010-06-10 00:00:00pages
194-206issue
2eissn
0303-7207issn
1872-8057pii
S0303-7207(10)00127-9journal_volume
321pub_type
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