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British Journal of Radiology (2007) 80, S23-S31
© 2007 British Institute of Radiology
doi: 10.1259/bjr/18237646
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Oxidative damage pathways in relation to normal tissue injury

W Zhao, PhD 1 D I Diz, PhD 2 and M E Robbins, PhD 1

Departments of 1 Radiation Oncology, Neurosurgery and Cancer Biology, Brain Tumor Center of Excellence and 2 Hypertension & Vascular Disease Center, General Surgery, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA

Correspondence: Mike E Robbins, Room # 409 NRC, Department of Radiation Oncology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. E-mail: mrobbins{at}wfubmc.edu


   Abstract
Top
 Abstract
Introduction
 Reactive oxygen/nitrogen oxide...
 Radiation-induced oxidative...
 Putative mediators of chronic...
 References
 
Given the increasing population of long-term cancer survivors, the need to mitigate or treat late effects has emerged as a primary area of radiation biology research. Once thought to be irreversible, radiation-induced late effects are now viewed as dynamic multicellular interactions between multiple cell types within a particular program that can be modulated. The molecular, cellular and biochemical pathways responsible for radiation-induced late morbidity remain ill-defined. This review provides data in support of the hypothesis that these late effects are driven, in part, by a chronic oxidative stress. Irradiating late responding normal tissues leads to chronic increases in reactive oxygen/reactive nitrogen oxide species that serve as intracellular signaling species to alter cell function/phenotype, resulting in chronic inflammation, organ dysfunction, and ultimate fibrosis and/or necrosis. Furthermore, we hypothesize that the effectiveness of renin-angiotensin system blockers in preventing or mitigating the severity of radiation-induced late effects reflects, in part, inhibition of reactive oxygen species generation and the resultant chronic oxidative stress. These findings provide a robust rationale for anti-inflammatory-based interventional therapies in the treatment of late normal tissue injury.


   Introduction
Top
 Abstract
 Introduction
Reactive oxygen/nitrogen oxide...
 Radiation-induced oxidative...
 Putative mediators of chronic...
 References
 
With 62% of adult and 77% of paediatric cancer patients surviving beyond 5 years as a result of continuing improvements in cancer therapy and health care, the long-term consequences of the primary therapeutic interventions have emerged as a significant risk. Study of these late effects has been targeted by the National Cancer Institute as one of the new areas of public health emphasis, particularly studying late effects (http://plan.cancer.gov). In radiation biology, the injury to normal tissue that develops in long-term survivors resulting from irradiation is now a primary area of radiation biology research.

In the last decade or so, our views on the pathogenesis of radiation-induced late normal tissue injury have changed markedly. The classic model of specific target cell clonogenic death leading to progressive and non-treatable reductions in organ function [1, 2] has been replaced with a new paradigm. Rather than simply a loss of normal cellular components, radiation-induced late effects are viewed now as a combination of loss of normal cellular function as well as an orchestrated response to injury that involves interactions between multiple cell types within a particular organ [3–5]. The normal cellular response to injury may in fact initiate a chronic active process that ultimately leads to progressive damage. Most importantly, however, evidence is emerging to suggest that this process can be modulated [6].

Following irradiation of normal tissues, an acute inflammatory response is observed, involving activation of stress-sensitive kinases, transcription factors [7] and increased production of inflammatory cytokines [8]. A chronic inflammatory/wound healing response developing over months to years is then responsible for persistent vascular and parenchymal cell dysfunction and cell loss. Recognition that the associated chronic overproduction of cytokines and growth factors results in fibrosis and/or necrosis [4] offers a novel approach to radiation-induced normal tissue morbidity. Recent findings support the hypothesis (for reviews see References [5, 9, 10]) that radiation-induced injury can be modulated by therapies directed at mitigating the cascade of events resulting from normal tissue injury. However, the mechanisms responsible for the clinical expression and progression of late, radiation-induced normal tissue injury, remain poorly understood.

A growing body of evidence suggests that the development and progression of radiation-induced late effects are driven, in part, by an acute and chronic oxidative stress [10]. This paper will provide first, updated data in support of this hypothesis and second, a rationale for anti-inflammatory-based interventional approaches directed at the treatment of late normal tissue injury.


   Reactive oxygen/nitrogen oxide species (ROS/RNOS)
Top
 Abstract
 Introduction
 Reactive oxygen/nitrogen oxide...
Radiation-induced oxidative...
 Putative mediators of chronic...
 References
 
All aerobic organisms produce ROS, partially reduced metabolites of molecular oxygen (dioxygen; O2) that have higher activities relative to molecular O2 [11, 12]. These include superoxide anion (O2•–) and hydrogen peroxide (H2O2), formed by one- and two-electron reductions of O2, respectively, as well as the hydroxyl radical (•OH) (Figure 1Go). O2•– is a free radical, defined as an atom or group of atoms possessing one or more unpaired electrons [13]. However, O2•– is not highly reactive, is unable to penetrate lipid membranes and thus is restricted to the intracellular compartment where it is generated. O2•– is primarily generated in the mitochondria as a result of leakage of electrons from the electron transport chain. In addition, O2•– is produced endogenously by flavoenzymes such as xanthine oxidase [14], lipoxygenase [15] and cyclooxygenase [16], as well as by the phagocytic [17] and the non phagocytic NAPDH oxidases [18]. O2•– is rapidly dismutated to H2O2 by the antioxidant enzyme superoxide dismutase (SOD). There are three known isoforms of SOD in eukaryotes; manganese SOD (MnSOD), located within the mitochondrial matrix [19], copper-zinc SOD (CuZnSOD), located in the cytoplasm, nucleus and lysosomes, and extracellular SOD (EC-SOD), released from cells into the extracellular space [20].


Figure 1
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  		Figure 1. ROS/RNOS, the primary antioxidant enzymes and antioxidants. Abbreviations are indicated in the text. GPx, glutathione peroxidase; GR, glutathione reductase; GSH, glutathione; GSSG, glutathione disulphide; MPO, myeloperoxidase; NADPH oxidase, nicotinamide adenine dinucleotide phosphate oxidase; NOS, nitric oxide synthase; Prx, peroxiredoxin; RNOS, reactive nitrogen oxide species; SOD, superoxide dismutase; TR, thioredoxin reductase; Trx, thioredoxin; Trx-S-S-Trx, thioredoxin disulfide.

 
H2O2 is not a free radical and is a weaker oxidizing agent than O2•–. Its importance lies in its ability to cross biological membranes and act as an intracellular messenger [21]. In addition to its generation through dismutation of O2•–, H2O2 can be formed by direct two-electron reduction of O2 catalysed by a variety of flavoprotein oxidases [22]. H2O2 serves as an intermediate in the generation of more reactive ROS, such as hypochlorous acid via the action of myeloperoxidase, present in the phagosomes of neutrophils [23]. In the presence of transition metals, H2O2 can give rise to the most reactive and toxic ROS, •OH by Fenton chemistry [24]. At high concentrations H2O2 is converted to water and O2 by catalase, localized predominantly in the peroxisomes in mammalian cells. The selenium-containing glutathione peroxidases (GPx) act to scavenge H2O2 at relatively low concentrations (for details see [10]). More recently, an additional family of antioxidant enzymes, the 2-Cys peroxiredoxins (2-Cys Prxs), have been recognized as important regulators of peroxide-mediated signalling cascades [25]. 2-Cys-Prxs are hypothesized to serve as "floodgates", keeping constitutive levels of H2O2 low, while permitting higher levels during signal transduction [26].

There is a growing appreciation of the important roles that the diatomic free radical nitric oxide (•NO) and reactive nitrogen oxide species (RNOS), formed from the reaction of •NO with molecular oxygen or O2•–, play in physiological and pathophysiological mechanisms [27, 28]. •NO is synthesized enzymatically from L-arginine by NO synthase (NOS) via electron transfer from NADPH. Three distinct isoforms of NOS have been identified (for reviews see [29, 30]). nNOS (also called Type 1, NOS-I and NOS-1) is localized predominantly in neuronal tissue. iNOS (also called Type II, NOS-II and NOS-2) is the inducible or calcium-independent isoform found in a wide range of cells and tissues, while eNOS (also called Type III, NOS-III and NOS-3) first identified in vascular endothelial cells is, like nNOS, a calcium-dependent, constitutively expressed isoform. At physiological concentrations •NO functions as an intracellular messenger; •NO can cross cell membranes and transmit signals to other cells [31]. •NO can also function as an excellent antioxidant; iron-catalyzed oxidation reactions are inhibited by •NO [32]. In pathophysiological situations where iNOS is upregulated, the most common RNOS generated in vivo are dintrogen trioxide (N2O3) and peroxynitrite (O = NOO–), both of which can induce nitrosative and oxidative stress [33]. In normal cells, ROS/RNOS are now recognized as important participants in intracellular signalling [34, 35], gene expression [36, 37] and physiological function [38]. ROS/RNOS generation is approximately in balance with antioxidant defences (antioxidants/antioxidant enzymes). Any imbalance between ROS/RNOS generation and antioxidant defences in favour of ROS/RNOS generation can create an oxidative stress.


   Radiation-induced oxidative stress
Top
 Abstract
 Introduction
 Reactive oxygen/nitrogen oxide...
 Radiation-induced oxidative...
Putative mediators of chronic...
 References
 
In vitro
Irradiating eukaryotic cells results in a rapid burst of ROS generated primarily as a result of ionization of water molecules [39]. The radicals and ROS generated include eaq–, H•, •OH, O2•– and H2O2. Due to their instability/reactivity eaq–, H•, and •OH react with target molecules within 1 ms of generation. In contrast, O2•– and H2O2 are relatively stable, and can persist for 101 s and >102 s, respectively, after irradiation of water [39]. Recent data indicate that in addition to the rapid burst of radicals and ROS observed immediately following radiation, cells can exhibit persistent and prolonged increases in ROS/RNOS over time frames ranging from several minutes to several days post-irradiation (for review see [40]); mitochondria appear to be the primary site of increased ROS/RNOS generation [41–43]. A growing body of literature supports a role for RNOS, particularly •NO, in these early radiation-induced signaling mechanisms [44–46].

In vivo
A radiation-induced increase in ROS/RNOS generation and/or an oxidative/nitrosative stress has also been observed in vivo. Due to the transient nature of the ROS/RNOS species generated, direct measurements are extremely challenging. Thus, the evidence has been derived primarily from studies showing increases in the formation of oxidized products. Whole body irradiation leads to increased markers of lipid peroxidation, including thiobarbituric acid reaction products (TBARs), 4-hydroxynonenal (4-HNE) and hexane in animal models and in patients [47–51]. Similar acute and/or chronic increases in oxidative/nitrosative stress have been noted in late responding normal tissues following localized organ irradiation; these are reviewed below.

Lung
Radiation-induced pneumonitis after unilateral irradiation of the rat lung leads to increased expression of NOS and •NO production [52]. More recent studies not only identified iNOS as the major source of •NO, but also identified radiation-induced nitrosative stress in the rat and mouse lung, evidenced by the presence of nitrotyrosine in the alveolar epithelium, macrophages and vascular endothelium [53, 54]. These findings have been confirmed in patients. Oxidative stress assessed using systemic markers of lipid peroxidation or by increased oxidized methionine in bronchoalveolar lavage fluid has been observed during and after the completion of radiation therapy in lung cancer patients [55–57].

Data indicative of a chronic oxidative stress in the irradiated lung have come from studies in the rat [58]. Hypoxia was identified in the rat lung 6 weeks after a single dose of 28 Gy using the hypoxia marker pimonidazole, and much earlier than the onset of functional or histopathological changes. This hypoxia became progressively more severe, such that at 6 months post-irradiation it was associated with a significant increase in macrophage activity, fibrosis, and increased breathing rate. Hypoxia has been shown to lead to increased ROS/RNOS production in various cell types [59, 60], due to increased ROS/RNOS generation and reduced antioxidant and/or antioxidant enzyme production [61]. Additional evidence in support of a radiation-induced chronic oxidative stress in the lung comes from recent studies in which increased lipid peroxidation, assessed in terms of malondialdehyde levels, was determined in the lungs of mice 15–20 weeks post-irradiation [62]. These increases in oxidative stress were not observed in irradiated lungs of transgenic mice overexpressing EC-SOD, which were protected against radiation-induced lung injury.

Central nervous system
Data published in the last 2–3 years suggest a primary role for chronic oxidative stress and ROS/RNOS in radiation-induced brain injury. Initial indirect evidence showed that irradiation of the rat brain inhibited hippocampal neurogenesis, associated with a marked increase in the number and activation status of microglia in the neurogenic zone [63]. Subsequent studies showed that inhibiting microglial activation using indomethacin restored hippocampal neurogenesis [64]. Direct experimental evidence for radiation-induced oxidative/nitrosative stress has been obtained from studies using neonatal and adult rats and mice. Fukuda et al [65] treated one hemisphere of postnatal day 8 rats or postnatal day 10 mice with a single dose of 4–12 Gy of 4 MV X-rays. Time-dependent increases in nitrotyrosine were observed in the subventricular zone and the granular cell layer of the dentate gyrus 2–12 h post-irradiation. An oxidative stress, evidenced as a significant increase in lipid peroxidation (measured using malondialdehyde) was noted in the adult male mouse hippocampus 2 weeks after brain irradiation with a single dose of 10 Gy [66]. More recently, Rola et al [67] have reported a chronic inflammatory response in the mouse dentate subgranular zone 9 months following high-LET brain irradiation; expression of the CCR2 receptor, important in neuroinflammation [68, 69], increased in the irradiated brains as compared with the sham-irradiated control brains.

Experimental data describing oxidative stress in the irradiated spinal cord are more limited. Increased expression of Hmox-1, a common marker of oxidative stress, has been observed in the irradiated rat spinal cord prior to the onset of myelopathy [70]. Moreover, a time- and dose-dependent increase in hypoxia, itself associated with oxidative stress, has been observed in the irradiated rat spinal cord prior to the onset of white matter necrosis [71].

Kidney
Chronic oxidative stress has been observed in the irradiated kidney. Robbins et al [72] adopted an indirect approach using immunohistochemical detection of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage [73]. Sham-irradiated kidneys showed little evidence of DNA oxidation over the 24 week experimental period. In marked contrast, localized kidney irradiation led to a marked, dose-independent increase in glomerular and tubular cell DNA oxidation, evident at the first time point studied, i.e., 4 weeks after irradiation, that was maintained for up to 24 weeks post-irradiation. Since the repair enzymes for 8-OHdG are present in the rat kidney [74], the failure of the kidney cell 8-OHdG staining to decrease suggested the presence of a chronic, persistent oxidative stress in the irradiated kidney for up to 24 weeks post-irradiation.

These data indicate that radiation may activate local mediators and thereby initiate continuous generation of ROS, causing chronic oxidative stress. In addition, there is a wealth of indirect data from studies using antioxidant/anti-inflammatory-based approaches that show prevention or mitigation of radiation-induced late normal tissue injury (see References [10, 75–77]). Indeed, the most successful interventional approach to reduce the severity of late radiation-induced injury, namely blockade of the renin-angiotensin system (RAS), may reflect, in part, inhibition of chronic oxidative stress.


   Putative mediators of chronic oxidative stress/inflammation: Ang II and ionizing radiation
Top
 Abstract
 Introduction
 Reactive oxygen/nitrogen oxide...
 Radiation-induced oxidative...
 Putative mediators of chronic...
References
 
The classic RAS is a complex blood-borne hormonal system in which systemic angiotensinogen (AGT, produced in the liver) is cleaved by renin (produced in the kidney) [78]. The resulting 10 amino acid peptide angiotensin (Ang) I is biologically inactive, and is cleaved by the angiotensin converting enzyme (ACE) in blood and on endothelial cells to release the effector eight amino acid peptide Ang II. Renin is not required for the generation of Ang II from AGT; additional enzymes can generate Ang II directly [79–81] and the regulation of other active peptide products of the RAS has been shown to be increasingly complex. Ang-(1–7) is formed from Ang I and Ang II [82] by tissue peptidases [83–85] and Ang IV is a product of Ang II via aminopeptidase-mediated hydrolysis [86]. Recently, the carboxypeptidase enzyme ACE2 has been discovered [87, 88] which unlike ACE, a dipeptidyl carboxypeptidase, removes a single C-terminal Leu residue from Ang I to generate Ang-(1–9), a peptide with no known function. However, Ang II is the preferred substrate for ACE2 [89] generating Ang-(1–7). Ang II produces the majority of its pro-hypertensive effects via binding to the type 1 (AT1) receptor, but increasing evidence suggests that the local tissue actions of the peptide involve both the AT1 and the type 2 (AT2) receptor [90, 91]. Ang-(1–7) acts at least in part via binding to the mas receptor [92]. As is the case with many peptide hormones, the receptors for both Ang II and Ang-(1–7) appear to be G protein coupled [93, 94]. Understanding the regulation of the balance of the three major biologically active peptides, Ang II, Ang IV and Ang-(1–7), in normal physiology and disease is key to dissecting out beneficial versus pathological effects of the RAS.

In addition to the systemic RAS, intra-organ RAS have been identified in the adipose tissue [95], brain [96], heart [97], kidney [98], pancreas [99], placenta [100] and the vasculature [97]. Thus, the beneficial effects of RAS blockade may include actions directly within these local tissues as well as indirectly from the improved haemodynamics associated with improved blood pressure (BP) reduction in hypertensive patients. [101]. AT1 receptor antagonists (AT1RA) or ACE inhibitors (ACEI) protect against age-related increases in BP and the associated deficits in heart, kidney and the vasculature and extend lifespan by 30–50% [102–104]. These treatments also mitigate late effects of irradiation in lung and kidney at subdepressor doses, suggesting that this therapeutic intervention is not a result of BP lowering actions. Moreover, the inability of other classes of antihypertensive agents to modulate radiation-induced injury and the absence of any data indicative of activation of the systemic RAS, has led to the hypothesis that RAS blockers are acting via inhibition of Ang II generated locally within the irradiated tissue. Other putative mechanisms have been proposed, including prevention of radiation-induced proliferation [105] or inhibition of a radiation-induced increase in TGFbeta [106]. We hypothesize that RAS blockade is acting to prevent and/or inhibit radiation-and Ang II-induced chronic oxidative stress [107]. In addition to its pleiotropic growth factor/cytokine properties, Ang II is a potent proinflammatory agent, mediating the release of proinflammatory mediators, including adhesion molecules, cytokines and chemokines [108] via activation of transcription factors, primarily AP-1 and NF{kappa}B [109]. A pathogenic link between Ang II and inflammation has been identified in peripheral tissues [108, 110, 111] and more recently in the brain [112, 113].

Ang II activates NADPH oxidase [114], which consists of membrane-bound components (gp91phox and p22phox) and cytosolic components (p47phox, p67phox and Rac1) that translocate to the membrane upon activation [115], to generate ROS. Ang II specifically phosphorylates p47phox, thus initiating the enzyme complex formation [116]. The O2•– anion production, catalysed by the transfer of a single electron from NADPH to molecular oxygen [18] as a result of the formation of the multi-subunit enzyme, is rapidly dismutated by SOD to H2O2, which is also a signalling molecule [21]. Although there are many sources of ROS in the cell, NADPH oxidases are the primary physiological ROS producers within the vasculature [117]. While two types of NADPH oxidase exist [18], it is not clear whether phagocytic NADPH oxidases, activated by pathogens [118] or non-phagocytic NADPH oxidases, constitutively producing ROS with both physiological [18] as well as pathophysiological effects [119], contribute to the late effects in normal cells following irradiation. In contrast to the interaction of Ang II with pro-inflammatory and oxidative processes, there is a close association of NADPH-diaphorase and Ang-(1–7) in brain areas associated with cardiovascular and neuroendocrine control [120]. Ang-(1–7) is elevated systemically during both ACEI and ATRA [121, 122]. Since Ang-(1–7) functions as an antagonist of Ang II [123], it is possible that the beneficial effects of RAS blockade on the late effects of radiation-induced injury reflects a shift in the balance between Ang II and Ang-(1–7) in favour of the latter. Regulating the relative levels of Ang II and Ang-(1–7) may be vital to developing effective therapeutic strategies to mitigate the late effects tissue injury.

Direct evidence implicating a role for RAS or NADPH oxidase-mediated oxidative stress in radiation-induced late effects is lacking. However, in vitro studies in our laboratory have generated data that suggest a role for both Ang II and NADPH oxidase in the radiation-induced increase in intracellular ROS observed in rat brain microvascular endothelial cells (Figure 2Go) in the hours immediately after exposure to radiation. Although a causal link between chronic oxidative stress, the RAS and radiation-induced late normal tissue injury remains to be established, a growing body of evidence supports the hypothesis that chronic oxidative stress in combination with activation of the local tissue RAS may serve to drive the progression of radiation-induced late effects. Chronic oxidative stress is an associated feature of ageing, and elevated gp91phox mRNA is present in brain hypothalamic tissue of older Sprague-Dawley rats [124] at time points where age-related dysfunction is present [125]. However, animals with low brain AGT do not exhibit age-related deficits in cardiovascular and metabolic function [125], even though gp91phox mRNA increases similarly in hypothalamic tissue of these animals as they age [124]. Thus, the late effect injury may require the synergistic actions of both systems. Indeed, the efficacy of RAS blockers to modulate radiation-induced late effects may also reflect an anti-inflammatory intervention that acts to prevent the propagation and/or maintenance of a radiation-induced chronic oxidative stress (Figure 3Go). Elucidating the specific pathogenic mechanisms involved offers the promise of optimizing antioxidative- or anti-inflammatory-based therapies, thus ensuring a significantly better quality of life for the growing number of long-term cancer survivors.


Figure 2
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  		Figure 2. Radiation-induced generation of ROS is abolished by preincubation with the antioxidant NAC, the AT1RA losartan and the NADPH oxidase inhibitors DPI and apocynin. Rat brain microvascular endothelial cells were irradiated with 0–10 Gy {gamma}-rays and ROS generation measured at 1 h post-irradiation using the oxidative-sensitive fluorescence probe H2DCFDA (A). In panels B and C, cells were pre-incubated with 5 mM NAC, 10 µM losartan, 10 µM DPI or apocynin for 30 min, respectively, prior to treatment with 10 Gy {gamma}-rays. Mean±SE; n = 3; *p<0.05.

 

Figure 3
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  		Figure 3. Putative pathways by which radiation-induced generation of ROS/RNOS can lead to chronic oxidative stress as well as activation of the intrinsic normal tissue RAS and generation of additional ROS resulting in the development and progression of radiation-induced late effects.

 


   Acknowledgments
 
This work was supported in part by grant numbers CA112593, CA122318, and HL51952.

Received for publication May 12, 2006. Revision received August 22, 2006. Accepted for publication September 28, 2006.


   References
Top
 Abstract
 Introduction
 Reactive oxygen/nitrogen oxide...
 Radiation-induced oxidative...
 Putative mediators of chronic...
 References
 

  1. Withers HR, Peters LJ, Kogelnik HS. The pathobiology of late effects in irradiation. In: Meyn RE, Withers HR, editors. Radiation biology in cancer research. New York, NY: Raven Press, 1980:439–48
  2. Rubin P, Casarett GW. Clinical radiation pathology as applied to curative radiotherapy. Cancer 1968;22:767–78.[CrossRef][Medline]
  3. Rubin P, Johnston CJ, Williams JP, McDonald S, Finkelstein JN. A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys 1995;33:99–109.[CrossRef][Medline]
  4. Denham JW, Hauer-Jensen M. The radiotherapeutic injury – a complex "wound". Radiother Oncol 2002;63:129–45.[CrossRef][Medline]
  5. Moulder J, Robbins MEC, Cohen EP, Hopewell JW, Ward WF. Pharmacologic modification of radiation-induced late normal tissue injury. In: Mittal BB, Purdy JA, Ang KK, editors. Radiation therapy. Norwell, MA: Kluwer, 1998: 129–51
  6. Stone HB, McBride WH, Coleman CN. Modifying normal tissue damage postirradiation. Radiat Res 2002;157:204–23.[CrossRef][Medline]
  7. Dent P, Yacoub A, Contessa J, Caron R, Amorino G, Valerie K, et al. Stress and radiation-induced activation of multiple intracellular signaling pathways. Radiat Res 2003;159:283–300.[Medline]
  8. Martin M, Lefaix JL, Delanian S. TGF-beta1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys 2000;47:277–90.[CrossRef][Medline]
  9. Moulder JE. Post-irradiation approaches to treatment of radiation injuries in the context of radiological terrorism and radiation accidents: a review. Int J Radiat Biol 2004;80:3–10.[CrossRef][Medline]
  10. Robbins MEC, Zhao W. Chronic oxidative stress and radiation-induced late normal tissue injury: a review. Int J Radiat Biol 2004;80:251–59.[CrossRef][Medline]
  11. Fridovich I. Fundamental aspects of reactive oxygen species, or what's the matter with oxygen? Ann NY Acad Sci 1999;893:13–18.[CrossRef][Medline]
  12. Nordberg J, Arner ESJ. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med 2001;31:1287–312.[CrossRef][Medline]
  13. Leigh GJ. Nomenclature of inorganic chemistry. Recommendations 1990. Oxford: Blackwell Scientific Publications
  14. Kuppusamy P, Zweier JL. Characterization of free radical generation by xanthine oxidase. Evidence for hydroxyl radical generation. J Biol Chem 1989;264:9880–4.[Abstract/Free Full Text]
  15. Baud L, Ardaillou R. Reactive oxygen species: production and role in the kidney. Am J Physiol Renal Fluid Electrolyte Physiol 1986;251:F765–6.[Abstract/Free Full Text]
  16. McIntyre M, Bohr DF, Dominiczak AF. Endothelial function in hypertension. Hypertension 1999;34:539–45.[Abstract/Free Full Text]
  17. Babior BM. NADPH oxidase: an update. Blood 1999;93:1464–76.[Free Full Text]
  18. Griendling K, Sorescu D, Ushio-Fukai M. NADPH oxidase: role in cardiovascular biology and disease. Circ Res 2000;86:494–501.[Abstract/Free Full Text]
  19. Weisiger RA, Fridovich I. Mitochondrial superoxide dismutase: site of synthesis and intramitochondrial localization. J Biol Chem 1973;248:4793–6.[Abstract/Free Full Text]
  20. Marklund SL. Human copper-containing superoxide dismutase of high molecular weight. Proc Natl Acad Sci USA 1982;79:7634–8.[Abstract/Free Full Text]
  21. Rhee SG, Chang TS, Bae YS, Lee SR, Kang SW. Cellular regulation by hydrogen peroxide. J Am Soc Nephrol 2003;14(Suppl. 3):S211–15.
  22. Massey V. Activation of molecular oxygen by flavins and flavoproteins. J Biol Chem 1994;269:22459–62.[Free Full Text]
  23. Winterbourn CC, Vissers MC, Kettle AJ. Myeloperoxidase. Curr Opin Hematol 2000;7:53–8.[CrossRef][Medline]
  24. Fridovich I. Superoxide anion radical (O2–.), superoxide dismutases, and related matters. J Biol Chem 1997;272:18515–17.[Free Full Text]
  25. Fujii J, Ikeda Y. Advances in our understanding of peroxiredoxin, a multifunctional, mammalian redox protein. Redox Rep 2002;7:123–30.[CrossRef][Medline]
  26. Wood ZA, Poole LB, Karplus PA. Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science 2003;300:650–3.[Abstract/Free Full Text]
  27. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109–42.[Medline]
  28. Gross SS, Wolin MS. Nitric oxide: Pathophysiological mechanisms. Annu Rev Physiol 1995;57:737–69.[CrossRef][Medline]
  29. Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochem J 1994;298:249–58.[Medline]
  30. Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J 2001;357:593–615.[CrossRef][Medline]
  31. Ignarro LJ. Heam-dependent activation of guanylate cyclase and cyclic GMP formation by endogenous nitric oxide: a unique transduction mechanism for transcellular signaling. Pharmacol Toxicol 1990;67:1–7.[Medline]
  32. Kanner J, Harel S, Granit R. Nitric oxide as an antioxidant. Arch Biochem Biophys 1991;289:130–6.[CrossRef][Medline]
  33. Wink DA, Mitchell JB. Chemical biology of nitric oxide: insights into regulatory, cytotoxic and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med 1998;25:434–56.[CrossRef][Medline]
  34. Forman HJ, Torres M, Fukuto J. Redox signaling. Mol Cell Biochem 2002;234–35:49–62.
  35. Nathan C. Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling. J Clin Invest 2003;111:769–78.[CrossRef][Medline]
  36. Pfeilschifter J, Eberhardt W, Beck K-F. Regulation of gene expression by nitric oxide. Pflungers Arch 2001;442:479–86.[CrossRef][Medline]
  37. Allen RG, Tresini M. Oxidative stress and gene regulation. Free Radic Biol Med 2000;28:463–99.[CrossRef][Medline]
  38. Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2001;82:47–95.
  39. Riley PA. Free radicals in biology: oxidative stress and the effects of ionizing radiation. Int J Radiat Biol 1994;65:27–33.[Medline]
  40. Spitz DR, Azzam EI, Li JJ, Gius D. Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: a unifying concept in stress response biology. Cancer Metastat Rev 2004;23:311–22.[CrossRef]
  41. Morales A, Miranda M, Sanchez-Reyes A, Biete A, Fernandez-Checa JC. Oxidative damage of mitochondrial and nuclear DNA induced by ionizing radiation in human hepatoblastoma cells. Int J Radiat Oncol Biol Phys 1998;42:191–203.[CrossRef][Medline]
  42. Lyng FM, Seymour CB, Mothersill C. Oxidative stress in cells exposed to low levels of ionizing radiation. Biochem Soc Trans 2001;29:350–3.[CrossRef][Medline]
  43. Leach JK, Van Tuyle G, Lin P-S, Schmidt-Ullrich R, Mikkelsen RB. Ionizing radiation-induced, mitochondria-dependent generation of reactive oxygen/nitrogen. Cancer Res 2001;61:3894–901.[Abstract/Free Full Text]
  44. Yoo J-C, Pae H-O, Choi B-M, Kim W-I, Kim J-D, Kim Y-M, et al. Ionizing radiation potentiates the induction of nitric oxide synthase by interferon-{gamma} (IFN-{gamma}) or IFN-{gamma} and lipopolysaccharide in BNL CL.2 murine embryonic liver cells: role of hydrogen peroxide. Free Radic Biol Med 2000;28:390–6.[CrossRef][Medline]
  45. Leach JK, Black SM, Schmidt-Ullrich RK, Mikkelsen RB. Activation of constitutive nitric-oxide synthase activity is an early signaling event induced by ionizing radiation. J Biol Chem 2002;277:15400–06.[Abstract/Free Full Text]
  46. Mikkelsen RB, Wardman P. Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms. Oncogene 2003;22:5734–54.[CrossRef][Medline]
  47. Clemens MR, Ladner C, Schmidt H, Ehninger G, Einsele H, Buhler E, et al. Decreased essential antioxidants and increased lipid hydroperoxides following high-dose radiochemotherapy. Free Radic Res Commun 1989;7:227–32.[Medline]
  48. Arterbery VE, Pryor WA, Jiang L, Sehnert SS, Foster WM, Abrams RA, et al. Breath ethane generation during clinical total body irradiation as a marker of oxygen-free-radical-mediated lipid peroxidation: a case study. Free Radic Biol Med 1994;17:569–76.[CrossRef][Medline]
  49. Ueda T, Toyoshima Y, Moritani T, Ri K, Otsuki N, Kushihashi T, et al. Protective effect of dipyridamole against lethality and lipid peroxidation in liver and spleen of the ddY mouse after whole-body irradiation. Int J Radiat Biol 1996;69:199–204.[CrossRef][Medline]
  50. Umegaki K, Sugisawa A, Shin SJ, Yamada K, Sano M. Different onsets of oxidative damage to DNA and lipids in bone marrow and liver in rats given total body irradiation. Free Radic Biol Med 2001;31:1066–74.[CrossRef][Medline]
  51. Lonergan PE, Martin DSD, Horrobin DF, Lynch MA. Neuroprotective effect of eicosapentaenoic acid in hippocampus of rats exposed to {gamma}-irradiation. J Biol Chem 2002;277:20804–11.[Abstract/Free Full Text]
  52. Nozaki Y, Hasegawa Y, Takeuchi A, Fan ZH, Nakashima I, Shimokata K. Nitric oxide as an inflammatory mediator of radiation pneumonitis in rats. Am J Physiol Lung Cell Mol Physiol 1997;272:L651–8.[Abstract/Free Full Text]
  53. Tsuji C, Shioya S, Hirota Y, Fukuyama N, Kurita D, Tanigaki T, et al. Increased production of nitrotyrosine in lung tissue of rats with radiation-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 2000;278:L719–25.[Abstract/Free Full Text]
  54. Giaid A, Lehnert SM, Chehayeb B, Chehayeb D, Kaplan I, Shenouda G. Inducible nitric oxide synthase and nitroytrosine in mice with radiation-induced lung damage. Am J Clin Oncol 2003;26:E67–72.[CrossRef][Medline]
  55. Jack CIA, Cottier B, Jackson MJ, Cassapi L, Fraser WD, Hind CRK. Indicators of free radical activity in patients developing radiation pneumonitis. Int J Radiat Oncol Biol Phys 1996;34:149–54.[CrossRef][Medline]
  56. Beinert T, Binder D, Stuschke M, Torres RA, Oehm C, Fleischhacker M, et al. Oxidant-induced lung injury in anticancer therapy. Eur J Med Res 1999;4:43–53.[Medline]
  57. Beinert T, Binder D, Oehm C, Ziemer S, Priem F, Stuschke M, et al. Further evidence for oxidant-induced vascular endothelial growth factor up-regulation in the bronchoalveolar lavage fluid of lung cancer patients undergoing radio-chemotherapy. J Cancer Res Clin Oncol 2000;126:352–6.[CrossRef][Medline]
  58. Vujaskovic Z, Anscher MS, Feng Q-F, Rabbani ZN, Amin K, Samulski TS, et al. Radiation-induced hypoxia may perpetuate late normal tissue injury. Int J Radiat Oncol Biol Phys 2001;50:851–5.[CrossRef][Medline]
  59. Duranteau J, Chandel NS, Kulisz A, Zhao Z, Schumaker PT. Intracellular signaling by reactive oxygen species during hypoxia in cardiomyocytes. J Biol Chem 1998;273:11619–24.[Abstract/Free Full Text]
  60. Killilea DW, Hester R, Balczon R, Babal P, Gillespie MN. Free radical production in hypoxic pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2000;279:L408–12.[Abstract/Free Full Text]
  61. Li C, Jackson R. Reactive species mechanisms of cellular hypoxia-reoxygenation injury. Am J Physiol Cell Physiol 2002;282:C227–41.[Abstract/Free Full Text]
  62. Kang SK, Rabbani ZN, Folz RJ, Golson ML, Huang H, Yu D, et al. Overexpression of extracellular superoxide dismutase protects mice from radiation-induced lung injury. Int J Radiat Oncol Biol Phys 2003;57:1056–66.[CrossRef][Medline]
  63. Monje ML, Mizumatsu S, Fike JR, Palmer T. Irradiation induced neural precursor-cell dysfunction. Nat Med 2002;8:955–61.[CrossRef][Medline]
  64. Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003;302:1760–5.[Abstract/Free Full Text]
  65. Fukuda H, Fukuda A, Zhu C, Korhonen L, Swanpalmer J, Hertzman S, et al. Irradiation-induced progenitor cell death in the developing brain is resistant to erythropoietin treatment and caspase inhibition. Cell Death Differ 2004;11:1166–78.[CrossRef][Medline]
  66. Limoli CL, Rola R, Giedzinski E, Mantha S, Huang T-T, Fike JR. Cell-density-dependent regulation of neural precursor cells function. Proc Natl Acad Sci USA 2004;101:16052–7.[Abstract/Free Full Text]
  67. Rola R, Sarkissian V, Obenaus A, Nelson GA, Otsuka S, Limoli CL, et al. High-LET radiation induces inflammation and persistent changes in markers of hippocampal neurogenesis. Radiat Res 2005;164:556–60.[CrossRef][Medline]
  68. Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol 2001;2:108–15.[CrossRef][Medline]
  69. Banisadr G, Queraud-Lesaux F, Boutterin MC, Pelaprat D, Zale B, Rostene W, et al. Distribution, cellular localization and functional role of CCR2 chemokine receptors in adult rat brain. J Neurochem 2002;81:257–69.[CrossRef][Medline]
  70. Tofilon PJ, Fike JR. The radioresponse of the central nervous system: a dynamic process. Radiat Res 2000;153:357–70.[CrossRef][Medline]
  71. Sawaya R, Rayford A, Kono S, Ang KK, Feng Y, Stephens LC, et al. Plasminogen activator inhibitor-1 in the pathogenesis of delayed radiation damage in rat spinal cord in vivo. J Neurosurg 1994;81:381–7.[CrossRef][Medline]
  72. Robbins MEC, Zhao W, Davis CS, Toyokuni S, Bonsib SM. Radiation-induced kidney injury: a role for chronic oxidative stress? Micron 2002;33:133–41.[CrossRef][Medline]
  73. Frank J, Pompella A, Biesalski HK. Histochemical visualization of oxidant stress. Free Radic Biol Med 2000;29:1096–105.[CrossRef][Medline]
  74. Kasai H, Nishimura S, Kurokawa Y, Hayashi Y. Oral administration of the renal carcinogen, potassium bromate, specifically produces 8-hydroxydeoxyguanosine in rat target organ DNA. Carcinogenesis 1987;8:1959–61.[Abstract/Free Full Text]
  75. Greenberger JS, Epperly MW, Gretton J, Jefferson M, Nie S, Bernarding M, et al. Radioprotective gene therapy. Curr Gene Ther 2003;3:183–95.[CrossRef][Medline]
  76. Moulder JE. Pharmacological intervention to prevent or ameliorate chronic radiation injuries. Semin Radiat Oncol 2003;2003:73–84.
  77. Anscher MS, Vujaskovic Z. Mechanisms and potential targets for prevention and treatment of normal tissue injury after radiation therapy. Semin Oncol 2005;32(Suppl. 3):S86–91.
  78. Lavoie JL, Sigmund CD. Minireview: overview of the renin-angiotensin system- an endocrine and paracrine system. Endocrinology 2003;144:2179–83.[Abstract/Free Full Text]
  79. Klickstein LB, Kaempfer CE, Wintroub BU. The granulocyte-angiotensin system. Angiotensin I-converting enzyme activity of cathepsin G. J Biol Chem 1982;257:15042–6.[Abstract/Free Full Text]
  80. Schiller PW, Demassieux S, Boucher R. Substrate specificity of tonin from rat submaxillary gland. Circ Res 1976;39:629–32.[Abstract/Free Full Text]
  81. Baltatu O, Nishimura H, Hoffman S, Stoltenburg G, Haulica ID, Lippoldt A, et al. High levels of human chymase expression in the pineal and pituitary glands. Brain Res 1997;752:269–78.[CrossRef][Medline]
  82. Chappell MC, Tallant EA, Brosnihan KB, Ferrario CM. Processing of angiotensin peptides by NG108-15 neuroblastoma x glioma hybrid cell line. Peptides 1990;11:375–80.[CrossRef][Medline]
  83. Yamamoto K, Chappell MC, Brosnihan KB, Ferrario CM. In vivo metabolism of angiotensin I by neutral endopeptidase (EC 3.4.24.11) in spontaneously hypertensive rats. Hypertension 1992;19:692–6.[Abstract/Free Full Text]
  84. Chappell MC, Tallant EA, Brosnihan KB, Ferrario CM. Conversion of angiotensin I to angiotensin-(1–7) by thimet oligopeptidase (EC 3.4.24.15) in vascular smooth muscle cells. J Vasc Biol Med 1995;5:129–37.
  85. Santos RAS, Brosnihan KB, Jacobsen DW, DiCorleto P, Ferrario CM. Production of Ang-(1–7) by human vascular endothelium. Hypertension 1992;19(Suppl. II):II-56–61.[Medline]
  86. Wright JW, Harding JW. The brain angiotensin system and extracellular matrix molecules in neural plasticity, learning, and memory. Prog Neurobiol 2004;72:263–93.[CrossRef][Medline]
  87. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 2000;87:E1–9.[Medline]
  88. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 2000;275:33238–43.[Abstract/Free Full Text]
  89. Burrell LM, Johnston CI, Tikellis C, Cooper ME. ACE2, a new regulator of the renin-angiotensin system. TRENDS Endocrinol Metab 2004;15:166–9.[CrossRef][Medline]
  90. Kambayashi Y, Bhardan S, Takahashi K, Tsuzuki S, Inui H, Hamakubo T, et al. Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J Biol Chem 1993;268:24543–6.[Abstract/Free Full Text]
  91. Mukoyama M, Nakajima M, Horiuchi M, Sasamura H, Pratt RE, Dzau VJ. Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven transmembrane receptors. J Biol Chem 1993;268:24539–42.[Abstract/Free Full Text]
  92. Chappell MC, Modrall JG, Diz DI, Ferrario CM. Novel aspects of the renal renin-angiotensin system: angiotensin-(1–7), ACE2 and blood pressure regulation. Contrib Nephrol 2004;143:77–89.[Medline]
  93. Kang J, Posner P, Sumners C. Angiotensin type II receptor stimulation of neuronal K+ currents involves an inhibitory G protein. Am J Physiol 1994;267:C1289–97.
  94. Zhang J, Pratt RE. The AT2 receptor selectively associates with Gi{alpha}2 and Gi{alpha}3 in the rat fetus. J Biol Chem 1996;271:15026–33.[Abstract/Free Full Text]
  95. Engeli S, Negrel R, Sharma AM. Physiology and pathophysiology of the adipose tissue renin-angiotensin system. Hypertension 2000;35:1270–7.[Abstract/Free Full Text]
  96. Davisson RL. Physiological genomic analysis of the brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 2003;285:R498–511.[Abstract/Free Full Text]
  97. Bader M, Peters J, Baltatu O, Muller DN, Luft FC, Ganten D. Tissue renin-angiotensinogen systems: new insights from experimental animal models in hypertension research. J Mol Med 2001;79:76–102.[CrossRef][Medline]
  98. Mulrow PJ. The intrarenal renin angiotensin. Curr Opin Nephrol Hyperten 1993;2:41–4.[Medline]
  99. Chappell MC, Diz DI, Gallagher PE. The renin-angiotensin system and the exocrine pancreas. J Panc Online 2001;2:33–9.
  100. Nielsen AH, Schauser KH, Poulsen K. The uteroplacental renin-angiotensin system. Placenta 2000;21:468–77.[CrossRef][Medline]
  101. Piepho RW. Overview of the angiotensin-converting enzyme inhibitors. Am J Health-Syst Pharm 2000;57:S3–7.[Abstract/Free Full Text]
  102. Basso N, Paglia N, Stella I, de Cavanagh EM, Ferder L, del Rosario Lores Arnaiz M, et al. Protective effect of the inhibition of the renin-angiotensin system on aging. Regul Pept 2005;128:247–52.[CrossRef][Medline]
  103. Kasper SO, Basso N, Kurnjek ML, Paglia N, Ferrario CM Ferder LF, et al. Divergent regulation of circulation and intra-renal renin-angiotensin systems in response to long-term blockade. Am J Nephrol 2005;25:335–41.[CrossRef][Medline]
  104. Tedesco MA, Ratti G, Di Salvo G, Natale F. Does the angiotensin II receptor antagonist losartan improve cognitive function? Drugs Aging 2002;19:723–32.[CrossRef][Medline]
  105. Molteni A, Moulder JE, Cohen EP, Ward WF, Fish BL, Taylor JM, et al. Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker. Int J Radiat Biol 2000;76:523–32.[CrossRef][Medline]
  106. Datta PK, Moulder JE, Fish BL, Cohen EP, Lianos EA. TGF-beta1 production in radiation nephropathy: role of angiotensin II. Int J Radiat Biol 1999;75:473–9.[CrossRef][Medline]
  107. Robbins ME, Diz DI. Pathogenic role of the renin-angiotensin system in modulating radiation-induced late effects. Int J Radiat Oncol Biol Phys 2006;64:6–12.[CrossRef][Medline]
  108. Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. Int J Biochem Cell Biol 2003;35:881–900.[CrossRef][Medline]
  109. Blume A, Herdegen T, Unger T. Angiotensin peptides and inducible transcription factors. J Mol Med 1999;77:339–57.[CrossRef][Medline]
  110. Ritz E, Haxsen V. Angiotensin II and oxidative stress: an unholy alliance. J Am Soc Nephrol 2003;14:2985–7.[Free Full Text]
  111. Touyz RM, Tabet F, Schiffrin EL. Redox-dependent signalling by angiotensin II and vascular remodelling in hypertension. Clin Exp Pharmacol Physiol 2003;30:860–6.[CrossRef][Medline]
  112. Saavedra JM, Ando H, Armando I, Baiardi G, Bregonzio C, Juorio A, et al. Anti-stress and anti-anxiety effects of centrally acting angiotensin II AT1 receptor antagonists. Regul Pept 2005;128:227–38.[CrossRef][Medline]
  113. Black PH. Stress and the inflammatory response: a review of neurogenic inflammation. Brain Behav Immun 2002;16:622–53.[CrossRef][Medline]
  114. Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 2004;4:181–9.[CrossRef][Medline]
  115. Rinckel L, Faris S, Hitt N, Kleinberg M. Rac1 disrupts p67phox/p47phox binding: a novel role of Rac in NADPH oxidase activation. Biochem Biophys Res Commun 1999;263:118–22.[CrossRef][Medline]
  116. Li J-M, Shah A. Intracellular localization and preassembly of the NADPH oxidase complex in cultured endothelial cells. J Biol Chem 2002;277:19952–60.[Abstract/Free Full Text]
  117. Griendling K, Minieri C, Ollerenshaw J, Alexander R. Angiotensin II stimulated NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 1994;74:1141–8.[Abstract/Free Full Text]
  118. Karlsson A, Dahlgren C. Assembly and activation of the neutrophil NADPH oxidase in granule membranes. Antioxid Redox Signal 2002;4:49–60.[CrossRef][Medline]
  119. Cai H, Griendling KK, Harrison DG. The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Res 2003;24:471–8.[CrossRef]
  120. Calka J, Block CH. Angiotensin-(1–7) and nitric oxide synthase in the hypothalamo-neuropophysial syste. Brain Bull 1993;30:677–85.[CrossRef]
  121. Kohara K, Brosnihan KB, Ferrario CM. Angiotensin-(1–7) in the spontaneously hypertensive rat. Peptides 1993;14:883–91.[CrossRef][Medline]
  122. Iyer SN, Chappell MC, Averill DB, Diz DI, Ferrario CM. Vasodepressor actions of Angiotensin-(1–7) unmasked during combined treatment with lisinopril and losartan. Hypertension 1998;31:699–705.[Abstract/Free Full Text]
  123. Ferrario CM, Chappell MC. Novel angiotensin peptides. Cell Mol Life Sci 2004;61:2720–7.[CrossRef][Medline]
  124. Garcia-Espinosa MA, Gallagher PE, Ferrario CM, Ganten D, Diz DI. Neprilysin and ACE2 regulation during aging in rats with low brain angiotensinogen. Hypertension 2005;46:830
  125. Kasper SO, Carter CS, Ferrario CM, Ganten D, Ferder LF, Sonntag WE, et al. Growth, metabolism, and blood pressure disturbances during aging in transgenic rats with altered brain renin-angiotensin system. Physiol Genomics 2004;23:311–17.



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