Stokes Research Institute, Department of Pediatrics, Children's Hospital of Philadelphia, and Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
FREE RADICALS SUCH AS SUPEROXIDE
and nitric oxide and reactive species such as peroxides and
peroxynitrite have been traditionally studied as mediators of cellular
and tissue pathology. However, free radicals and reactive species
generated enzymatically or through chemical interactions, usually
present at low concentrations during normal cellular metabolism, have
also been shown to regulate signal transduction (reviewed in Refs.
3-5, 7). There is a growing list of
transcription factors, receptors, and proteins involved in signal
transduction that are sensitive to regulation by reactive species
(1, 6, 8). These observations provide compelling evidence
that the production of cytokines, growth factors, and other proteins
essential for cellular homeostasis are influenced in part by reactive species.
In this issue of the American Journal of Physiology-Lung
Cellular and Molecular Biology, Kosmidou et al. (2)
provide evidence that hydrogen peroxide or other reactive species
increase the production of vascular endothelial growth factor (VEGF) in
differentiated skeletal myotubes. The authors probed further and
demonstrated that the effect of hydrogen peroxide was due to activation
of the phosphoinositide 3-kinase pathway and downstream by
phosphorylation and activation of Akt. The data imply that activation
and phosphorylation of Ser473 of Akt is redox sensitive.
The downstream effects of Akt pathway activation involve the regulation
of endothelial nitric oxide activity and activation of several proteins
involved in blocking apoptosis and promoting cellular survival.
These observations may relate to the potential beneficial effects of
exercise. Increased production of reactive intermediates is thought to
occur during exercise, and it is possible that the production of
reactive species mediates an adaptive response in skeletal muscle cells
against oxidative stress by upregulating cell survival pathways such as
the Akt pathway. The ability of reactive species to trigger release of
growth factors such as VEGF may add to the armament of cells to
withstand more intense workloads and oxidative stress. In addition, the
reactive species-mediated increase in the production of VEGF and
potentially of other growth factors during exercise may lead to an
increase in angiogenesis and muscle growth. The data also imply that
reactive species-mediated regulation of growth factor production and
regulation of cell survival pathways may be a critical component of
preconditioning and adaptation to stress, an area of scientific
endeavor that holds great promise in producing new fascinating and
interesting information.
Reactive species react with a number of biological molecules,
their reactivity being regulated by the concentration of reactants, second-order rate constants, compartmentalization, and, in part, the
presence of redox-sensitive amino acid residues such as cysteine and
tyrosine. The relative ease in oxidizing and reducing these exquisitely
sensitive redox-regulated residues in kinases, transcription factors,
ion channels, and receptors appears to be instrumental in facilitating
the role of reactive species in signal transduction. It is expected
that in the near future, studies similar to the one by Kosmidou et al.
(2) in specific cell systems will elucidate the
potential roles of reactive species in the regulation of
critical signal transduction events and cellular homeostasis.
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Address for reprint requests and other correspondence: H. Ischiropoulos, Stokes Research Institute, Children's Hospital of Philadelphia, 416D Abramson Center, 34th St. and Civic Center Blvd., Philadelphia, PA 19104-4318 (E-mail: ischirop{at}mail.med.upenn.edu).
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1.
Irani, K,
Xia Y,
Zweier JL,
Sollott SJ,
Der CJ,
Fearon ER,
Sundaresan M,
Finkel T,
and
Goldschmidt-Clermont PJ.
Mitogenic signaling mediated by oxidants in ras-transformed fibroblasts.
Science
275:
1649-1652,
1997
2.
Kosmidou, I,
Xagorari A,
Roussos C,
and
Papapetropoulos A.
Reactive oxygen species stimulate VEGF production from C2C12 skeletal myotubes through a PI3-K/Akt pathway.
Am J Physiol Lung Cell Mol Physiol
280:
L585-L592,
2001
3.
Lander, HM.
An essential role for free radicals and derived species in signal transduction.
FASEB J
11:
118-124,
1997
4.
Patel, RP,
Moelliring D,
Murphy-Ullrich J,
Jo H,
Beckman JS,
and
Darley-Usmar VM.
Cell signaling by reactive nitrogen and oxygen species in atherosclerosis.
Free Radic Biol Med
28:
1780-1794,
2000[ISI][Medline].
5.
Sen, CK,
and
Packer L.
Antioxidant and redox regulation of gene transcription.
FASEB J
10:
709-720,
1996
6.
Sundaresan, M,
Yu ZX,
Ferrans VJ,
Irani K,
and
Finkel T.
Requirement for generation of H2O2 for platelet-derived growth factor signal transduction.
Science
270:
296-299,
1995[Abstract].
7.
Suzuki, YJ,
Forman HJ,
and
Sevanian A.
Oxidants as stimulators of signal transduction.
Free Radic Biol Med
22:
269-285,
1997[ISI][Medline].
8.
True, AL,
Rahman A,
and
Malik AB.
Activation of NF-B induced by H2O2 and TNF-
and its effects on ICAM-1 expression in endothelial cells.
Am J Physiol Lung Cell Mol Physiol
279:
L302-L311,
2000