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Peroxynitrite induces senescence and apoptosis of red blood cells through the activation of aspartyl and cysteinyl proteases
Author(s) -
Matarrese Paola,
Straface Elisabetta,
Pietraforte Donatella,
Gambardella Lucrezia,
Vona Rosa,
Maccaglia Alessandro,
Minetti Maurizio,
Malorni Walter
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2450fje
Subject(s) - peroxynitrite , apoptosis , chemistry , reactive oxygen species , microbiology and biotechnology , superoxide , nitric oxide , proteases , cathepsin , programmed cell death , oxidative stress , biochemistry , senescence , caspase , biology , enzyme , organic chemistry
ABSTRACT 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 μ‐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, μ‐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.