X-Message-Number: 25736
Date: Mon, 28 Feb 2005 05:19:55 -0800 (PST)
From: Doug Skrecky <>
Subject: peroxynitrate may have a role in SIPS induced "aging"

[Stress Induced Premature Senescence (SIPS) may occur under conditions of
exposure to inflamation inducing molecules, as well as to relatively
stable free radicals such as superoxide. Peroxynitrite may be
one of the mediators of this phenomina. Increased peroxynitrite scavenging
by ebselen has partly reversed SIPS in a diabetic model.]

FASEB J. 2005 Jan 13; [Epub ahead of print]
Peroxynitrite induces senescence and apoptosis of red blood cells through
the activation of aspartyl and cysteinyl proteases.
  Changes in the oxidative status of erythrocytes can reduce cell
lifetime, oxygen transport, and delivery capacity to peripheral tissues
and have been associated with a plethora of human diseases. Among
reactive oxygen and nitrogen species of importance in red blood cell
(RBC) homeostasis, superoxide and nitric oxide radicals play a key role.
In the present work, we evaluated subcellular effects induced by
peroxynitrite, the product of the fast reaction between superoxide and
nitric oxide. Peroxynitrite induced 1) oxidation of oxyhemoglobin to
methemoglobin, 2) cytoskeleton rearrangement, 3) ultrastructural
alterations, and 4) altered expression of band-3 and decreased expression
of glycophorin A. With respect to control cells, this occurred in a
significantly higher percentage of human RBC (~40%). The presence of
antioxidants inhibited these modifications. Furthermore, besides these
senescence-associated changes, other important modifications, absent in
control RBC and usually associated with apoptotic cell death, were
detected in a small but significant subset of peroxynitrite-exposed RBC
(~7%). Active protease cathepsin E and mu-calpain increased; activation
of caspase 2 and caspase 3 was detected; and phosphatidylserine
externalization, an early marker of apoptosis, was observed. Conversely,
inhibition of cathepsin E, mu-calpain, as well as caspase 2 and 3 by
specific inhibitors resulted in a significant impairment of erythrocyte
"apoptosis" Altogether, these results indicate that peroxynitrite, a
milestone of redox-mediated damage in human pathology, can hijack human
RBC toward senescence and apoptosis by a mechanism involving both
cysteinyl and aspartyl proteases.

Circ Res. 2004 Feb 20;94(3):377-84. Epub 2003 Dec 11.
Prevention and reversal of premature endothelial cell senescence and
vasculopathy in obesity-induced diabetes by ebselen.
  Although the accelerated atherosclerosis and premature aging of the
cardiovascular system in patients with metabolic syndrome have been
appreciated, the mechanisms of their development and potential
therapeutic interventions remain unresolved. Our previous studies
implicated advanced glycosylation end products in development of premature
senescence preventable with a peroxynitrite scavenger, ebselen.
Therefore, the effect of ebselen on endothelial senescence and
vasculopathy in a model of metabolic syndrome--Zucker diabetic rats
(ZDF)--was investigated. Ebselen decreased the abundance of
3-nitrotyrosine-modified proteins in ZDF rats. A 6-fold increase in the
number of senescent endothelial cells in 22-week-old ZDF was prevented by
ebselen. Development of vasculopathy, as collectively judged by the
acetylcholine-induced vasorelaxation, NO production, angiogenic
competence, and number of circulating microparticles, was almost
completely prevented when ebselen was administered from 8 to 22 weeks and
partially reversed when the treatment interval was 13 to 22 weeks. In
conclusion, premature senescence of endothelial cells is progressively
rampant in ZDF rats and is associated with the signs of severe
vasculopathy. In addition, prevention of premature
senescence of vascular endothelium through controlled decrease in
nitrotyrosine formation was chronologically associated with the
amelioration of vasculopathy, lending support to the idea of the
pathogenetic role of premature senescence of endothelial cells in
diabetic macrovasculopathy.

Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=25736