Apoptosis Signal-Regulating Kinase 1 Mediates Cellular Senescence Induced by High Glucose in Endothelial Cells

T. Yokoi, K. Fukuo, O. Yasuda, M. Hotta, J. Miyazaki, Y. Takemura, H. Kawamoto, H. Ichijo, T. Ogihara
2006 Diabetes  
Vascular ageing is accelerated in patients with diabetes. However, the underlying mechanism remains unclear. Here, we show that high glucose induces activation of apoptosis signal-regulating kinase 1 (ASK1), an apoptosisinducing signal that mediates endothelial cell senescence induced by hyperglycemia. High glucose induced a timedependent increase in the levels of ASK1 expression and its activity in human umbilical vein endothelial cells (HUVECs). Incubation of endothelial cells with high
more » ... lls with high glucose increased the proportion of cells expressing senescence-associated ␤-galactosidase (SA-␤-gal) activity. However, transfection with an adenoviral construct including a dominant negative form of ASK1 gene significantly inhibited SA-␤-gal activity induced by high glucose. In addition, infection with an adenoviral construct expressing the constitutively active ASK1 gene directly induced an increase in the levels of SA-␤-gal activity. Activation of the ASK1 signal also enhanced plasminogen activator inhibitor-1 (PAI-1) expression in HUVECs. Induction of senescent endothelial cells in aortas and elevation of plasma PAI-1 levels were observed in streptozotocin (STZ) diabetic mice, whereas these changes induced by STZ were attenuated in ASK1-knockout mice. Our results suggest that hyperglycemia accelerates endothelial cell senescence and upregulation of PAI-1 expression through activation of the ASK1 signal. Thus, ASK1 may be a new therapeutic target to prevent vascular ageing and thrombosis in diabetic patients.
doi:10.2337/db05-1607 pmid:16731828 fatcat:5sfzpgvtebhzrlj4q26ekr47ua