Acta Physiol 2014, 210, 2–4
ExActa Dealing with radicals Ask a non-physiologist neighbour with a career outside a laboratory, hospital or lecture hall: most probably, you will find that ‘radical’ or ‘reactive’ is not a term usually associated with an ageing population. For the biomedical scientist, however, the association between ageing and age-related pathologies and an accumulation of reactive species (or an accumulation of the damage done by them) has become a paradigm only recently challenged (Liochev 2013). Pathophysiological processes that reactive chemical compounds have been blamed with are, however, not limited to the ageing process: rather, vascular pathologies, atherosclerosis and Parkinson’s disease are just as well among them as are psychopathologies or diseases that result from the toxic damage of recreationally abused substances such as alcohol or tobacco. So who are the suspects, and what is their physiological role? Reactive oxygen (ROS) and reactive nitrogen (RNS) species are the main classes of transient reactive small molecules relevant for human and vertebrate physiology (Nathan & Cunningham-Bussel, 2013). Hydrogen sulphide (H2S), its anion [HS ] as well as carbon monoxide (CO) are additional endogenous small reactive signalling molecules. For these reactive intermediates to be generated in tissues or cells, their relative instability and reactive potential necessitated the evolutionary development of protective mechanisms to control RXS generation and contain them to their relevant compartments, as they would otherwise cause cellular damage: Redox homeostasis constitutes a conditio sine qua non for the physiological use of RXS in signal transduction, transcriptional control and functional cellular responses. Novo & Parola (2008) as well as Pourova et.al, (2010) have, in an illustrative and concise yet comprehensive way, subsumed RXS generation, function and pathophysiology in the human organism. Reactive oxygen species have largely been considered by-products of oxygen metabolism in aerobia mainly from either NADPH oxidase action or mitochondrial metabolism, among them free radicals sporting unpaired electrons such as [OH] or [O2 ], or reactive non-radical compounds such as H2O2 or HOCl. However, not only professional phagocytes do intentionally generate ROS, as had been assumed (Lambeth 2004). RNS are produced from the reaction of nitric oxide (NO) with superoxide (O-) to form peroxynitrite (ONOO ). 2
RXS are, in general, considered to be dangerous for living cells, tissues and thus organisms for their ability to change DNA structure, cause lipid peroxidation and oxidative damage to amino acids within peptides or proteins, and to oxidize enzymatic cofactors. Besides and/or through their effects on protein structure and function and catalytic enzyme activity, RXS may alter cytoskeletal organization and impair cell signal transduction (Pacher et al. 2007). As RXS have moved to the centre of interdisciplinary attention, chemistry has supplied us with tools and information that move RXS research forward: small-molecule fluorescent probes, for example, have been developed for the detection of reactive species through oxidative cleavage reactions compatible with living systems, which enable repeated in vivo imaging (Chan et al. 2012). On the other hand, not everyone who looks like a radical is one indeed, as reported for certain reactive intermediates unexpectedly stabilized by the presence of a remote anionic site in the same molecule (Forbes 2013). RXS involvement in physiology and pathophysiology is diverse, covering functional areas such as skeletal muscle metabolism (Petersen et al. 2012) (Kanazashi et al. 2013) (Wadley 2013) (Makanae et al. 2013), renal function (Sw€ ard & Rippe 2012) (Carlstr€ om et al. 2013) and hemodynamics (Ahmeda & Johns 2012) (Ahmeda et al. 2013) (Liu et al. 2013), cardiac contractility and function (Sripetchwandee et al. 2013), and, of course, the broad field of ischaemia-reperfusion injury (Sedoris et al. 2012) (Wang et al. 2013). Interesting results have recently been shown by Eleawa et al. (2013), demonstrating that androgen effects on cardiac function may depend on a reduction in oxidative stress, while RXS generally play a major role in the regulation of cardiac contractility (Perjes et al. 2012). Recent results from Phalitakul et al. (2013) establish a functional connection between adipokine secretion and endothelial cell dysfunction mediated by ROS which may be highly relevant for therapeutic interventions targeting the critical link between obesity and cardiovascular disease (Zahradka 2013a). RXS effects on ion channel expression and regulation are hardly limited to the cardiovascular system, although TRPA channels, a TRP subgroup (see also Kukkonen 2012) mainly expressed on peptidergic C-fibres in the pain pathway that register noxious
© 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12193
Acta Physiol 2014, 210, 2–4
chemicals, and whose sustained activation is involved in neuropathic pain, are apparently aberrantly activated when ROS contribute to the non-enzymatic formation of TRPA1 ligands (Koivisto 2012). The vast array of high-quality results on RXS function and pathophysiology has not led to the breakthrough of antioxidant therapeutic approaches that had been projected a couple of years ago (Steinhubl 2008). However, considering these data only would not reflect the important role played by RXS in applied pharmacology: The therapeutic effect of a high number of currently used drugs relies on ROS generation, sensitization of cells to RXS, or on the induction or inhibition of specific cellular ROS production or catabolism.
Conflict of interest None.
A. Bondke Persson and P. B. Persson Institute of Vegetative Physiology, Charite-Universitaetsmedizin Berlin, Berlin, Germany E-mail: [email protected]
References Ahmeda, A.F. & Johns, E.J. 2012. The regulation of blood perfusion in the renal cortex and medulla by reactive oxygen species and nitric oxide in the anaesthetised rat. Acta Physiol (Oxf) 204, 443–450. Ahmeda, A.F., Rae, M.G. & Johns, E.J. 2013. Effect of reactive oxygen species and nitric oxide in the neural control of intrarenal haemodynamics in anaesthetized normotensive rats. Acta Physiol (Oxf) 209, 156–166. Carlstr€ om, M., Brown, R.D., Yang, T., Hezel, M., Larsson, E., Scheffer, P.G., Teerlink, T., Lundberg, J.O. & Persson, A.E. 2013. L-arginine or tempol supplementation improves renal and cardiovascular function in rats with reduced renal mass and chronic high salt intake. Acta Physiol (Oxf) 207, 732–741. Chan, J., Dodani, S.C. & Chang, C.J. 2012. Reaction-based small-molecule fluorescent probes for chemoselective bioimaging. Nat Chem 4, 973–984. Eleawa, S.M., Sakr, H.F., Hussein, A.M., Assiri, A.S., Bayoumy, N.M., & Alkhateeb, M. 2013. Effect of testosterone replacement therapy on cardiac performance and oxidative stress in orchidectomized rats. Acta Physiol (Oxf) 209, 136–147. Forbes, M.D.E. 2013. Reactive intermediates: radicals with multiple personalities. Nat Chem 5, 447–449. Kanazashi, M., Okumura, Y., Al-Nassan, S., Murakami, S., Kondo, H., Nagatomo, F., Fujita, N., Ishihara, A., Roy,
Ex Acta
· A Bondke Persson and P B Persson
R.R. & Fujino, H. 2013. Protective effects of astaxanthin on capillary regression in atrophied soleus muscle of rats. Acta Physiol (Oxf) 207, 405–415. Koivisto, A. 2012. Sustained TRPA1 activation in vivo. Acta Physiol (Oxf) 204, 248–254. Kukkonen, J.P. 2012. International symposium on G-proteincoupled receptors (GPCRs), TRP (ion) channels and lipid signalling - GPCR-Helsinki 2010. Acta Physiol (Oxf) 204, 148–150. Lambeth, J.D. 2004. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4, 181–189. Liochev, S.I. 2013. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med 60, 1–4. Liu, N., Patzak, A. & Sendeski, M.M. 2013. Nitric oxide and reactive oxygen species in renal medulla pathophysiology - so small yet so special: the renal medulla. Acta Physiol (Oxf) 208, 144–147. Makanae, Y., Kawada, S., Sasaki, K., Nakazato, K. & Ishii, N. 2013. Vitamin C administration attenuates overloadinduced skeletal muscle hypertrophy in rats. Acta Physiol (Oxf) 208, 57–65. Nathan, C. & Cunningham-Bussel, A. 2013. Beyond oxidative stress: an immunologist’s guide to reactive oxygen species. Nat Rev Immunol 13, 349–361. Novo, E. & Parola, M. 2008. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair. 1, 5. Pacher, P., Beckman, J.S. & Liaudet, L. 2007. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87, 315–424. Perjes, A., Kubin, A.M., K onyi, A., Szabados, S., Czir aki, A., Skoumal, R., Ruskoaho, H. & Szokodi, I. 2012. Physiological regulation of cardiac contractility by endogenous reactive oxygen species. Acta Physiol (Oxf) 205, 26–40. Petersen, A.C., McKenna, M.J., Medved, I., Murphy, K.T., Brown, M.J., Della Gatta, P. & Cameron-Smith, D. 2012. Infusion with the antioxidant N-acetylcysteine attenuates early adaptive responses to exercise in human skeletal muscle. Acta Physiol (Oxf) 204, 382–392. Phalitakul, S., Okada, M., Hara, Y. & Yamawaki, H. 2013. Vaspin prevents methylglyoxal-induced apoptosis in human vascular endothelial cells by inhibiting reactive oxygen species generation. Acta Physiol (Oxf) 209, 212–219. Pourova, J., Kottova, M., Voprsalova, M. & Pour, M. 2010. Reactive oxygen and nitrogen species in normal physiological processes. Acta Physiol (Oxf) 198, 15–35. Sedoris, K.C., Gozal, E., Ovechkin, A.V., Theile, A.R. & Roberts, A.M. 2012. Interplay of endothelial and inducible nitric oxide synthases modulates the vascular response to ischaemia-reperfusion in the rabbit lung. Acta Physiol (Oxf) 204, 331–343. Sripetchwandee, J., Kenknight, S.B., Sanit, J., Chattipakorn, S. & Chattipakorn, N. 2013. Blockade of mitochondrial calcium uniporter prevents cardiac mitochondrial dysfunction caused by iron overload. Acta Physiol (Oxf). doi: 10. 1111/apha.12162. Steinhubl, S.R. 2008. Why have antioxidants failed in clinical trials? Am J Cardiol 101, 14D–19D.
© 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12193
3
A Bondke Persson and P B Persson
· Ex Acta
Sw€ard, P. & Rippe, B. 2012. Acute and sustained actions of hyperglycaemia on endothelial and glomerular barrier permeability. Acta Physiol (Oxf) 204, 294–307. Wadley, G.D. 2013. A role for reactive oxygen species in the regulation of skeletal muscle hypertrophy. Acta Physiol (Oxf) 208, 9–10. Wang, Y., Li, Y., Wang, C., Ai, J., Dong, X., Huang, H., Feng, Z., Pan, Y., Lin, Y., Wang, B. & Yao, L. 2013. L-3-
4
Acta Physiol 2014, 210, 2–4 n-butylphthalide protects rats’ cardiomyocytes from ischemia/reperfusion- induced apoptosis by affecting the mitochondrial apoptosis pathway. Acta Physiol. doi: 10.1111/ apha.12186. Zahradka, P. 2013a. Inhibition of NADPH oxidase by vaspin may prevent progression of atherosclerosis. Acta Physiol (Oxf) 209, 195–198.
© 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12193
ExActa Dealing with radicals Ask a non-physiologist neighbour with a career outside a laboratory, hospital or lecture hall: most probably, you will find that ‘radical’ or ‘reactive’ is not a term usually associated with an ageing population. For the biomedical scientist, however, the association between ageing and age-related pathologies and an accumulation of reactive species (or an accumulation of the damage done by them) has become a paradigm only recently challenged (Liochev 2013). Pathophysiological processes that reactive chemical compounds have been blamed with are, however, not limited to the ageing process: rather, vascular pathologies, atherosclerosis and Parkinson’s disease are just as well among them as are psychopathologies or diseases that result from the toxic damage of recreationally abused substances such as alcohol or tobacco. So who are the suspects, and what is their physiological role? Reactive oxygen (ROS) and reactive nitrogen (RNS) species are the main classes of transient reactive small molecules relevant for human and vertebrate physiology (Nathan & Cunningham-Bussel, 2013). Hydrogen sulphide (H2S), its anion [HS ] as well as carbon monoxide (CO) are additional endogenous small reactive signalling molecules. For these reactive intermediates to be generated in tissues or cells, their relative instability and reactive potential necessitated the evolutionary development of protective mechanisms to control RXS generation and contain them to their relevant compartments, as they would otherwise cause cellular damage: Redox homeostasis constitutes a conditio sine qua non for the physiological use of RXS in signal transduction, transcriptional control and functional cellular responses. Novo & Parola (2008) as well as Pourova et.al, (2010) have, in an illustrative and concise yet comprehensive way, subsumed RXS generation, function and pathophysiology in the human organism. Reactive oxygen species have largely been considered by-products of oxygen metabolism in aerobia mainly from either NADPH oxidase action or mitochondrial metabolism, among them free radicals sporting unpaired electrons such as [OH] or [O2 ], or reactive non-radical compounds such as H2O2 or HOCl. However, not only professional phagocytes do intentionally generate ROS, as had been assumed (Lambeth 2004). RNS are produced from the reaction of nitric oxide (NO) with superoxide (O-) to form peroxynitrite (ONOO ). 2
RXS are, in general, considered to be dangerous for living cells, tissues and thus organisms for their ability to change DNA structure, cause lipid peroxidation and oxidative damage to amino acids within peptides or proteins, and to oxidize enzymatic cofactors. Besides and/or through their effects on protein structure and function and catalytic enzyme activity, RXS may alter cytoskeletal organization and impair cell signal transduction (Pacher et al. 2007). As RXS have moved to the centre of interdisciplinary attention, chemistry has supplied us with tools and information that move RXS research forward: small-molecule fluorescent probes, for example, have been developed for the detection of reactive species through oxidative cleavage reactions compatible with living systems, which enable repeated in vivo imaging (Chan et al. 2012). On the other hand, not everyone who looks like a radical is one indeed, as reported for certain reactive intermediates unexpectedly stabilized by the presence of a remote anionic site in the same molecule (Forbes 2013). RXS involvement in physiology and pathophysiology is diverse, covering functional areas such as skeletal muscle metabolism (Petersen et al. 2012) (Kanazashi et al. 2013) (Wadley 2013) (Makanae et al. 2013), renal function (Sw€ ard & Rippe 2012) (Carlstr€ om et al. 2013) and hemodynamics (Ahmeda & Johns 2012) (Ahmeda et al. 2013) (Liu et al. 2013), cardiac contractility and function (Sripetchwandee et al. 2013), and, of course, the broad field of ischaemia-reperfusion injury (Sedoris et al. 2012) (Wang et al. 2013). Interesting results have recently been shown by Eleawa et al. (2013), demonstrating that androgen effects on cardiac function may depend on a reduction in oxidative stress, while RXS generally play a major role in the regulation of cardiac contractility (Perjes et al. 2012). Recent results from Phalitakul et al. (2013) establish a functional connection between adipokine secretion and endothelial cell dysfunction mediated by ROS which may be highly relevant for therapeutic interventions targeting the critical link between obesity and cardiovascular disease (Zahradka 2013a). RXS effects on ion channel expression and regulation are hardly limited to the cardiovascular system, although TRPA channels, a TRP subgroup (see also Kukkonen 2012) mainly expressed on peptidergic C-fibres in the pain pathway that register noxious
© 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12193
Acta Physiol 2014, 210, 2–4
chemicals, and whose sustained activation is involved in neuropathic pain, are apparently aberrantly activated when ROS contribute to the non-enzymatic formation of TRPA1 ligands (Koivisto 2012). The vast array of high-quality results on RXS function and pathophysiology has not led to the breakthrough of antioxidant therapeutic approaches that had been projected a couple of years ago (Steinhubl 2008). However, considering these data only would not reflect the important role played by RXS in applied pharmacology: The therapeutic effect of a high number of currently used drugs relies on ROS generation, sensitization of cells to RXS, or on the induction or inhibition of specific cellular ROS production or catabolism.
Conflict of interest None.
A. Bondke Persson and P. B. Persson Institute of Vegetative Physiology, Charite-Universitaetsmedizin Berlin, Berlin, Germany E-mail: [email protected]
References Ahmeda, A.F. & Johns, E.J. 2012. The regulation of blood perfusion in the renal cortex and medulla by reactive oxygen species and nitric oxide in the anaesthetised rat. Acta Physiol (Oxf) 204, 443–450. Ahmeda, A.F., Rae, M.G. & Johns, E.J. 2013. Effect of reactive oxygen species and nitric oxide in the neural control of intrarenal haemodynamics in anaesthetized normotensive rats. Acta Physiol (Oxf) 209, 156–166. Carlstr€ om, M., Brown, R.D., Yang, T., Hezel, M., Larsson, E., Scheffer, P.G., Teerlink, T., Lundberg, J.O. & Persson, A.E. 2013. L-arginine or tempol supplementation improves renal and cardiovascular function in rats with reduced renal mass and chronic high salt intake. Acta Physiol (Oxf) 207, 732–741. Chan, J., Dodani, S.C. & Chang, C.J. 2012. Reaction-based small-molecule fluorescent probes for chemoselective bioimaging. Nat Chem 4, 973–984. Eleawa, S.M., Sakr, H.F., Hussein, A.M., Assiri, A.S., Bayoumy, N.M., & Alkhateeb, M. 2013. Effect of testosterone replacement therapy on cardiac performance and oxidative stress in orchidectomized rats. Acta Physiol (Oxf) 209, 136–147. Forbes, M.D.E. 2013. Reactive intermediates: radicals with multiple personalities. Nat Chem 5, 447–449. Kanazashi, M., Okumura, Y., Al-Nassan, S., Murakami, S., Kondo, H., Nagatomo, F., Fujita, N., Ishihara, A., Roy,
Ex Acta
· A Bondke Persson and P B Persson
R.R. & Fujino, H. 2013. Protective effects of astaxanthin on capillary regression in atrophied soleus muscle of rats. Acta Physiol (Oxf) 207, 405–415. Koivisto, A. 2012. Sustained TRPA1 activation in vivo. Acta Physiol (Oxf) 204, 248–254. Kukkonen, J.P. 2012. International symposium on G-proteincoupled receptors (GPCRs), TRP (ion) channels and lipid signalling - GPCR-Helsinki 2010. Acta Physiol (Oxf) 204, 148–150. Lambeth, J.D. 2004. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4, 181–189. Liochev, S.I. 2013. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med 60, 1–4. Liu, N., Patzak, A. & Sendeski, M.M. 2013. Nitric oxide and reactive oxygen species in renal medulla pathophysiology - so small yet so special: the renal medulla. Acta Physiol (Oxf) 208, 144–147. Makanae, Y., Kawada, S., Sasaki, K., Nakazato, K. & Ishii, N. 2013. Vitamin C administration attenuates overloadinduced skeletal muscle hypertrophy in rats. Acta Physiol (Oxf) 208, 57–65. Nathan, C. & Cunningham-Bussel, A. 2013. Beyond oxidative stress: an immunologist’s guide to reactive oxygen species. Nat Rev Immunol 13, 349–361. Novo, E. & Parola, M. 2008. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair. 1, 5. Pacher, P., Beckman, J.S. & Liaudet, L. 2007. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87, 315–424. Perjes, A., Kubin, A.M., K onyi, A., Szabados, S., Czir aki, A., Skoumal, R., Ruskoaho, H. & Szokodi, I. 2012. Physiological regulation of cardiac contractility by endogenous reactive oxygen species. Acta Physiol (Oxf) 205, 26–40. Petersen, A.C., McKenna, M.J., Medved, I., Murphy, K.T., Brown, M.J., Della Gatta, P. & Cameron-Smith, D. 2012. Infusion with the antioxidant N-acetylcysteine attenuates early adaptive responses to exercise in human skeletal muscle. Acta Physiol (Oxf) 204, 382–392. Phalitakul, S., Okada, M., Hara, Y. & Yamawaki, H. 2013. Vaspin prevents methylglyoxal-induced apoptosis in human vascular endothelial cells by inhibiting reactive oxygen species generation. Acta Physiol (Oxf) 209, 212–219. Pourova, J., Kottova, M., Voprsalova, M. & Pour, M. 2010. Reactive oxygen and nitrogen species in normal physiological processes. Acta Physiol (Oxf) 198, 15–35. Sedoris, K.C., Gozal, E., Ovechkin, A.V., Theile, A.R. & Roberts, A.M. 2012. Interplay of endothelial and inducible nitric oxide synthases modulates the vascular response to ischaemia-reperfusion in the rabbit lung. Acta Physiol (Oxf) 204, 331–343. Sripetchwandee, J., Kenknight, S.B., Sanit, J., Chattipakorn, S. & Chattipakorn, N. 2013. Blockade of mitochondrial calcium uniporter prevents cardiac mitochondrial dysfunction caused by iron overload. Acta Physiol (Oxf). doi: 10. 1111/apha.12162. Steinhubl, S.R. 2008. Why have antioxidants failed in clinical trials? Am J Cardiol 101, 14D–19D.
© 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12193
3
A Bondke Persson and P B Persson
· Ex Acta
Sw€ard, P. & Rippe, B. 2012. Acute and sustained actions of hyperglycaemia on endothelial and glomerular barrier permeability. Acta Physiol (Oxf) 204, 294–307. Wadley, G.D. 2013. A role for reactive oxygen species in the regulation of skeletal muscle hypertrophy. Acta Physiol (Oxf) 208, 9–10. Wang, Y., Li, Y., Wang, C., Ai, J., Dong, X., Huang, H., Feng, Z., Pan, Y., Lin, Y., Wang, B. & Yao, L. 2013. L-3-
4
Acta Physiol 2014, 210, 2–4 n-butylphthalide protects rats’ cardiomyocytes from ischemia/reperfusion- induced apoptosis by affecting the mitochondrial apoptosis pathway. Acta Physiol. doi: 10.1111/ apha.12186. Zahradka, P. 2013a. Inhibition of NADPH oxidase by vaspin may prevent progression of atherosclerosis. Acta Physiol (Oxf) 209, 195–198.
© 2013 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd, doi: 10.1111/apha.12193
