FOXO3a governs early and late apoptotic endothelial programs during elevated glucose through mitochondrial and caspase signaling.
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.
Hou
Jinling
J
Division of Cellular and Molecular Cerebral Ischemia, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Chong
Zhao Zhong
ZZ
Shang
Yan Chen
YC
Maiese
Kenneth
K
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000502:physiology*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism*; D053938:DNA Fragmentation; D004727:Endothelium / Q000187:drug effects / Q000201:enzymology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005947:Glucose; D006943:Hyperglycemia; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors
D001786:Blood Glucose; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D005947:Glucose