Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells.
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 apoptosis-inducing signal that mediates endothelial cell senescence induced by hyperglycemia. High glucose induced a time-dependent increase in the levels of ASK1 expression and its activity in human umbilical vein endothelial cells (HUVECs). Incubation of endothelial cells with high glucose increased the proportion of cells expressing senescence-associated beta-galactosidase (SA-beta-gal) activity. However, transfection with an adenoviral construct including a dominant negative form of ASK1 gene significantly inhibited SA-beta-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-beta-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.
Yokoi
Toyohiko
T
Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Fukuo
Keisuke
K
Yasuda
Osamu
O
Hotta
Mizuo
M
Miyazaki
Junichi
J
Takemura
Yukihiro
Y
Kawamoto
Hidenobu
H
Ichijo
Hidenori
H
Ogihara
Toshio
T
D000256:Adenoviridae / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin / Q000633:toxicity; D013997:Time Factors; D014162:Transfection
D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D013311:Streptozocin; D048848:MAP Kinase Kinase Kinase 5; D005947:Glucose