EDITORIAL FOCUS
Reactive species and signal transduction

Harry Ischiropoulos

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


    ARTICLE
TOP
ARTICLE
REFERENCES

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.


    FOOTNOTES

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).


    REFERENCES
TOP
ARTICLE
REFERENCES

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[Abstract/Free Full Text].

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[Abstract/Free Full Text].

3.   Lander, HM. An essential role for free radicals and derived species in signal transduction. FASEB J 11: 118-124, 1997[Abstract/Free Full Text].

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[Abstract/Free Full Text].

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-kappa B induced by H2O2 and TNF-alpha and its effects on ICAM-1 expression in endothelial cells. Am J Physiol Lung Cell Mol Physiol 279: L302-L311, 2000[Abstract/Free Full Text].


Am J Physiol Lung Cell Mol Physiol 280(4):L583-L584
1040-0605/01 $5.00 Copyright © 2001 the American Physiological Society