Insulin-like growth factor-1 receptor activation prevents high glucose-induced mitochondrial dysfunction, cytochrome-c release and apoptosis.
Vascular disease is the leading cause of morbidity and mortality in patients with diabetes. Persistent hyperglycemia--the dominant metabolic derangement of diabetes, can cause endothelial cell apoptosis. Diabetes is often associated with low insulin like growth factor-1 (IGF-1), and the latter state has been linked to adverse risk profile and increased cardiovascular disease incidence. Since IGF-1 acts as an important survival factor for multiple cell types, this study was to investigate whether IGF-1 exert regulatory effects on high glucose-induced apoptosis of vascular endothelial cells. Exposure to high glucose dose- and time-dependently induced apoptotic changes (e.g., DNA fragmentation, altered mitochondrial membrane potential, and cytochrome-c release) in human umbilical vein endothelial cells (HUVECs). Addition of IGF-1 blocked the high glucose effect in a manner dependent on expression of IGF-1 receptor (IGF-1R) since silencing IGF-1R with small interference RNA could diminish the IGF-1' anti-apoptosis effect. Our findings show that enhanced IGF-1 signaling inhibits glucose-induced apoptosis in HUVECs by reducing mitochondrial dysfunction, and maintaining the mitochondrial retention of cytochrome-c. These results may have therapeutic implications in preventing/reducing diabetes associated endothelial dysfunction.
Li
Yangxin
Y
Texas Heart Institute and The University of Texas Medical School, Houston, TX 77030, USA. Yangxin_li@yahoo.com
Wu
Hanjing
H
Khardori
Romesh
R
Song
Yao-Hua
YH
Lu
Yao Wei
YW
Geng
Yong-Jian
YJ
D017209:Apoptosis; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism*; D053938:DNA Fragmentation; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000819:agonists* / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics
D034741:RNA, Small Interfering; D007334:Insulin-Like Growth Factor I; D045304:Cytochromes c; D005947:Glucose