Published online before print May 16, 2002, doi: 10.1161/01.RES.0000022161.42655.98
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Submitted on December 5, 2001
Revised on March 19, 2002
Accepted on April 30, 2002
Glycated Collagen I Induces Premature Senescence-Like Phenotypic Changes in Endothelial Cells
Jun Chen ;
From the Departments of Medicine, Physiology and Biophysics, and Program in Biomedical Engineering (J.C., S.V.B., D.M.G, D.J.H., H.L., M.S.G.), State University of New York, Stony Brook, NY; and the Department of Pharmacology (S.S.G.), Weill Medical College at Cornell University, New York, NY.
* To whom correspondence should be addressed. E-mail: mgoligorsky{at}mail.som.sunysb.edu.
Diabetic vasculopathy is central to the development of diverse cardiovascular, renal, retinal, and neurological complications of diabetes. We previously demonstrated that growth of endothelial cells on glycated extracellular matrix proteins (collagen and matrigel) triggers a significant decrease in cell proliferation. In the present study, we show that early-passage human umbilical vein endothelial cells (HUVECs) grown on glycated collagen (GC) express hallmarks of premature cell senescence, ie, increase in the proportion of cells expressing senescence-associated ß-galactosidase activity, apoptotic rate, and p53 and p14AFR expression, but in contrast to replicative senescence, display neither attrition of telomeres nor decrease in telomerase activity. An increased frequency of prematurely senescent cells was similarly observed in vivo in aortae of young Zucker diabetic rats, compared with lean controls. NO production by HUVECs grown on GC was decreased, despite a 3-fold increase in eNOS expression and was associated with the increased nitrotyrosine-modified proteins. Development of premature senescence of HUVECs on GC could be prevented and reversed by treatments with the peroxynitrite scavenger, ebselen, eNOS intermediate N
-hydroxy-L-arginine (NOHA), or superoxide dismutase mimetic Mn-TBAP. Concomitant with the reversal of senescence, ebselen, and NOHA each restored NO production to levels observed with HUVECs grown on unmodified collagen. Our findings indicate that diabetes mellitus in vivo and GC exposure in vitro elicit premature senescence of the vascular endothelium, a process with distinct pathogenetic mechanisms. Premature senescence of the vascular endothelium is hypothesized to be an important contributor to diabetic vasculopathy and a consequence of reduced NO availability, peroxynitrite, and/or superoxide excess.
Key words: senescence • telomerase • nitric oxide • superoxide • p53 • p14ARF
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