HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yokoi, T. Articles by Ogihara, T. Search for Related Content PubMed PubMed Citation Articles by Yokoi, T. Articles by Ogihara, T. Social Bookmarking                What's this?

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

¹ Department of Geriatric Medicine, Osaka University Gradate School of Medicine, Osaka, Japan
² Department of Food Sciences and Nutrition, School of Human Environmental Sciences, Mukogawa Women’s University, Nishinomiya, Japan
³ Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Osaka, Japan
⁴ Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan

Address correspondence and reprint requests to Keisuke Fukuo, MD, PhD, Department of Food Sciences and Nutrition, School of Human Environmental Sciences, Mukogawa Women’s University, 6-46 Ikebiraki-cho, Nishinomiya, Hyogo, 663-8558, Japan. E-mail: fukuo{at}mwu.mukogawa-u.ac.jp

Abbreviations: ASK1, apoptosis signal-regulating kinase 1; CA-ASK1, constitutively active form of ASK1; DN-ASK1, dominant negative form of ASK1; HUVEC, human umbilical vein endothelial cell; MAP, mitogen-activated protein; PAI-1, plasminogen activator inhibitor-1; SA-ß-gal, senescence-associated ß-galactosidase; STZ, streptozotocin

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 ß-galactosidase (SA-ß-gal) activity. However, transfection with an adenoviral construct including a dominant negative form of ASK1 gene significantly inhibited SA-ß-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-ß-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.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Held, H.C. Gerstein, S. Yusuf, F. Zhao, L. Hilbrich, C. Anderson, P. Sleight, K. Teo, and for the ONTARGET/TRANSCEND Investigators Glucose Levels Predict Hospitalization for Congestive Heart Failure in Patients at High Cardiovascular Risk Circulation, March 20, 2007; 115(11): 1371 - 1375. [Abstract] [Full Text] [PDF]

				T. Minamino and I. Komuro Vascular Cell Senescence: Contribution to Atherosclerosis Circ. Res., January 5, 2007; 100(1): 15 - 26. [Abstract] [Full Text] [PDF]