HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 292/5/H2040    most recent 01316.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Kobayashi-Miura, M. Articles by Yodoi, J. Search for Related Content PubMed PubMed Citation Articles by Kobayashi-Miura, M. Articles by Yodoi, J.

CALL FOR PAPERS
Oxygen Sensing: Life and Death of a Cell

Oxygen sensing and redox signaling: the role of thioredoxin in embryonic development and cardiac diseases

¹Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan; ²Department of Cardiovascular Medicine, Kishiwada City Hospital, Kishiwada City, Japan; and ³Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, Japan

	ABSTRACT

TOP ABSTRACT GRANTS REFERENCES

 
It is important to regulate the oxygen concentration and scavenge oxygen radicals throughout the life of animals. In mammalian embryos, proper oxygen concentration gradually increases in utero and excessive oxygen is rather toxic during early embryonic development. Reactive oxygen species (ROS) are generated as by-products in the respiratory system and increased under inflammatory conditions. In the pathogenesis of a variety of adult human diseases such as cancer and cardiovascular disorders, ROS cause an enhancement of tissue injuries. ROS promote not only the development of atherosclerosis but also tissue injury during the reperfusion process. The thioredoxin (TRX) system is one of the most important mechanisms for regulating the redox balance. TRX is a small redox active protein distributed ubiquitously in various mammalian tissues and cells. TRX acts as not only an antioxidant but also an anti-inflammatory and an antiapoptotic protein. TRX is induced by oxidative stress and released from cells in response to oxidative stress. In various human diseases, the serum/plasma level of TRX is a well-recognized biomarker of oxidative stress. Here we discuss the roles of TRX on oxygen stress and redox regulation from different perspectives, in embryogenesis and in adult diseases focusing on cardiac disorders.

reactive oxygen species; oxidative stress

It is well known that embryos stop development at a certain stage during in vitro fertilization in mammals (47). It is suggested that the cell block is a consequence, at least in part, of free radical damage incurred by embryos (63).

During the early postimplantation period, rodent embryos survive under relatively anaerobic conditions in utero and are most sensitive to environmental oxygen concentrations. Proper oxygen concentration increases as development proceeds in the mammalian early postimplantation embryonic period. As mammalian embryos are vulnerable to oxygen in the period, excessive oxygen is toxic and causes developmental anomalies. Later, they acquire resistance and tolerance to oxygen once the uteroplacental circulation is established (86).

Reactive oxygen species (ROS) such as hydroxyl radicals and superoxide induce different cellular effects depending on their concentration and the cell type. When high levels of ROS are generated by exo- and endogenous sources, the redox balance is perturbed, and cells are shifted into a state of oxidative stress (93).

In adult animals, the cardiovascular organ is one of the most vulnerable to ROS for circulating and supplying oxygen from the heart. In the human body, oxidative stress is known to be involved in various cardiac disorders (62, 116). The pathological changes in acute coronary syndrome such as acute myocardial infarction and unstable angina are suggested to be a disruption of atherosclerotic plaque and subsequent hemagglutination (27, 65). Oxidative stress is deeply involved in the process mediated by oxidized low-density lipoprotein (LDL) (96). Atherosclerosis and vasospasm are the major pathogenses preceding ischemic heart disease. The generation of ROS has been reported following ischemia-reperfusion injury in various organs (18, 19, 28).

TRX as a Redox-Regulating System

To protect them from oxidative stress, cells possess a set of antioxidative enzymes and systems, which maintain the intracellular ROS at proper levels. The thioredoxin (TRX) system is one of the major intracellular redox regulating systems (Fig. 1) (38). The TRX system contains many antioxidative proteins such as TRX, mitochondrial TRX-2, their reductases (TRXRs), and peroxiredoxins. Several of the proteins are essential to embryogenesis because some TRX family knockout mice are embryonically lethal (13, 44, 68, 89).

View larger version (35K): [in this window] [in a new window]   Fig. 1. Biological functions of thioredoxin (TRX). TRX is a redox-acting protein that exchanges disulfide with dithiol to maintain the reducing status of various molecules. The TRX system (TRX, TRX reductase, and NADPH) reduces peroxiredoxin or oxidized proteins. In the cytoplasm, TRX interacts with intracellular signal transduction. Oxidative stress induces TRX expression. In the nucleus, TRX has interactions with transcription factors or TRX-binding protein-2 (TBP-2)/vitamin D3-upregulated protein-1 (VDUP-1). Oxidized TRX or truncated TRX was released from cells. S, oxidized cysteine residue (S-S, disulfide bond); SH, reduced cysteine residue; ASK-1, apoptosis signal-regulating kinase 1; AP-1, activator protein-1; CRE, AMP responsive element; ARE, antioxidant responsive element; SP-1, specificity protein-1 binding site; Ref-1, redox factor-1.

TRX was originally cloned from Escherichia coli (59) and is a redox active protein well conserved from procaryotes to mammals (39). Human TRX was reported as adult T-cell leukemia-derived factor in transformed cells with human T-cell leukemia virus type I (113, 119). Human TRX is a small 12-kDa protein consisting of 105 amino acids. It has a conserved CXXC construct at its active site that exchanges disulfide with dithiol to maintain the reducing status of various molecules. The reducing activity of TRX is controlled by NADPH and TRXR (59). TRX is also induced by a wide variety of stress conditions such as UV or X-ray irradiation, viral infection, ischemia-reperfusion, and drugs, such as antineoplastic agents (80, 81). It also acts as a radical scavenger in cooperation with peroxiredoxin (117). TRX is known to have diverse properties such as anti-inflammating and antiapoptotic effects (78, 102), which are, in some part, related to its regulation of intracellular signal transduction. TRX regulates various intracellular signaling pathways. TRX inhibits apoptosis signal-regulating kinase 1 (a MAPK kinase kinase) signals to suppress apoptosis (100). P38 MAPK is also suppressed by TRX (31). The DNA binding of transcription factors such as nuclear factor-B (NF-B), activator protein-1, and p53 are known to be regulated by TRX (36, 91, 129).

Nishiyama et al. (87, 88) identified several TRX-binding proteins. TRX-binding protein (TBP)-1 is a cytosolic component of phagocyte NADPH oxidase (88), and TBP-2 is identical to vitamin D₃ upregulated protein 1 (87). TBP-2 can bind only to the reduced form of TRX. TRX with amutation at the redox active site fails to bind with TBP-2. Another report suggested that the overexpression of TBP-2 inhibits the TRX-dependent suppression of c-Jun NH₂-terminal kinase activity and the interaction of TRX with apoptosis signal-regulating kinase 1 (48). TBP-2 is a kind of endogenous negative modulator of TRX.

Mechanism of Oxygen Sensing

There are several specialized oxygen-sensing systems consisting of resistance pulmonary arteries, ductus arteriosus, carotid body, neuroepithelial body, systemic arteries, fetal adrenomedullary cells, and fetoplacental arteries in mammals, which optimize oxygen uptake and delivery (2, 134). As it is essential to maintain the proper oxygen condition, oxygen sensing is absolutely essential for animals to respond to environmental changes. Some oxygen-sensing systems such as the ductus arteriosus, fetal adrenomedullary cells, and fetoplacental arteries of the fetus are not found in the adult due to a difference in oxygen utilization. The carotid body, which is located at the bifurcation of the carotid artery, responds to a decrease in the arterial oxygen concentration (hypoxemia) by increasing spiking activity in the sinus nerve. Glomus cells work as chemoreceptors in the carotid body and sense hypoxemia (66, 67). In the pulmonary artery, hypoxia activates oxygen sensors of the pulmonary artery smooth muscle cells (3, 17). Pulmonary neuroepithelial bodies have specialized structures composed of clusters of innervated amine and peptide-containing cells and are presumed to be the airway chemoreceptors that are located preferentially at or near the airway bifurcation in most species (8, 14, 61, 90).

After these cells are exposed to acute hypoxia in vivo or in vitro, they secrete amine (serotonin) (15, 60). In their oxygen-sensing systems, hypoxia changes the redox couples and activated ROS generation (69). Mitochondria are important regulators of cellular redox status and are candidates for oxygen sensors. The major intracellular sources of ROS and peroxides are cytochrome-based oxidases, such as NADPH and NADH oxidases, and the electron transport chain in mitochondria (137). ROS are now recognized as important mediators of cellular signaling. Several kinases and sarcolemmal K⁺ channels are redox sensitive and modulated by ROS (1, 24, 97). Intracellular redox signaling is a major downstream mediator of oxygen sensing regulating vascular tone. The diffusible ROS from the mitochondria, NADPH oxidase, or redox couples may control K⁺ channel gating. The outward K⁺ current is then reduced and the membrane depolarized, leading to Ca²⁺ influx through the voltage-dependent Ca²⁺ channels and vasoconstriction. The same redox signaling may control Ca²⁺ release from the sarcoplasmic reticulum. The Ca²⁺ stored in the sarcoplasmic reticulum, in turn, is replaced by Ca²⁺ entering through store-operated channels. Rho kinase augments the response of actin-myosin at all levels of cytosolic Ca²⁺. It is very likely that the mechanisms by which hypoxia is sensed at the molecular level are highly conserved and tightly regulated (2, 69, 134).

Hypoxia promotes vasoconstriction in the fetoplacental vasculature (42). It has been suggested that hypoxia induces fetoplacental vasoconstriction by inhibiting K⁺ channel activity, thereby causing the Ca²⁺ channel activity in the smooth muscle of small fetoplacental arteries (29). The adrenomedullary chromaffin cells in the rodent fetus, which also secrete catecholamine in response to hypoxic stimuli, possess a developmentally regulated oxygen-sensing mechanism similar to neural crest-derived cells, such as glomus cells in the carotid body (120, 121). However, these hypoxic-sensing mechanisms, which are present in the neonate, disappear in juvenile (postnatal, 13–20 days) adrenomedullary chromaffin cells. This is consistent with a model that oxygen sensing in these cells is a developmentally regulated process (121). In the fetus, the blood from the right ventricle bypasses the pulmonary circulation through the ductus arteriosus. At birth, oxygen tension increases through the newly expanded lungs and provokes the closing of the ductus arteriosus. The ductus arteriosus in the fetus exhibits an opposite response to contraction when the oxygen level rises at birth; that is, normoxic contraction is explained partly by the inhibition of K⁺ channels, membrane depolarization, and Ca²⁺ entry in the smooth muscle cells of the ductus arteriosus (125).

There has been no previous report that TRX itself has a direct role in oxygen sensing. TRX regulates hypoxia-inducible factor, one of the major mediators of oxygen sensing (43). The HIFs are regulated at the level of protein stability and transcriptional activity in an oxygen-dependent manner by prolyl and asparaginyl hydroxylation, respectively. In another report, the "TRX-like fold" structure of a protein disulfide isomerase and other chaperone proteins was found to be associated with oxygen-sensing ability (10). It is possible that TRX plays some role in oxygen sensing.

Oxygen Regulation During Normal Embryonic Development

During in vitro fertilization, embryonic development is arrested at some specific stage, which coincides with the earliest period of embryonic gene expression. The stage varies with the species (the 2-cell stage in mice and rats, the 4-cell stage in pigs, the 8-cell stage in humans, and the 16-cell stage in cows and sheeps) (47). The two-cell block in mice is the earliest phenomenon that has a relationship with oxidative stress on development after fertilization. In the event of the two-cell block, supplementating the medium with a radical scavenger such as reduced glutathione can improve embryonic development in vitro (63). Natsuyama et al. (83) also showed that superoxide dismutase (SOD), a free radical scavenger, and TRX, a potent protein disulfide reductase, release the mouse two-cell stage developmental block in vitro (83).

During the early postimplantation period, rodent embryos survive in a relatively hypoxic environment in utero. It is believed that the early period of organogenesis, which coincides with the early postimplantation period, is when the embryo is most sensitive and vulnerable to environmental insults (58). It becomes resistant to oxygen stress when exposed to a higher oxygen pressure after the uteroplacental circulation is established. Cultures of whole rodent embryos are widely used to investigate the mechanisms of normal and abnormal development as well as the embryotoxic effects of environmental agents (13a). When rodent embryos at the headfold and neurulation stages [embryonic day (E) 7.5–9.5 in mice and E9–11 in rats] are cultivated in vitro, they are grown under a relatively low-oxygen concentration (5–10% oxygen) because their growth and differentiation are significantly perturbed and various developmental anomalies are induced if they are grown under higher oxygen concentrations (85). These results mean that early postimplantation rodent embryos are vulnerable to oxygen stress. They become less sensitive to oxygen as they develop, and their oxygen requirement increases. In fact, the oxygen requirement of explanted embryos increases to 95% by E10 in mice and E11 in rats (76, 85). Chen et al. (7) showed that rat embryos treated with 45% oxygen from E9 exhibited severe abnormalities, most prominently neural tube closure defects, whereas those treated on E10–11 were morphologically normal. The yolk sac of the placenta supports the respiration and nutrition of the embryo during the early postimplantation period and takes oxygen and nutrients from the blood circulation by diffusion through the chorion and visceral yolk sac. Around E9.5 in mice and E11.0 in rats, the yolk sac of the placenta regresses and the definitive allantoic placenta takes over an increasing share of respiratory and nutrient exchanges. Coinciding with such a transition in the uteroplacental circulation, embryos would be acutely exposed to a higher oxygen pressure, which benefits rapid growth and differentiation, and therefore need to acquire a defense mechanism against oxidative stress. In mouse embryos cultivated from E7.5 for 48 h, severe abnormalities developed such as open neural tube, microcephaly, and no rotation (57). However, the embryos cultivated from E8.5 are already tolerant against 25% oxygen. It is possible that mouse embryos acquire resistance to oxidative stress after E7.5.

Redox regulation plays a role in various tissues and stages during normal embryonic development. Salas-Vidal et al. (101) showed that ROS production is essential for normal mouse embryogenesis, and an increase in ROS of specific cells mediates apoptosis that is required for cell elimination during embryonic morphogenesis. Nucleoredoxin, a TRX-related redox-regulating protein, inhibits Wnt--catenin signaling through Dishevelled (Dvl). Wnt signaling is essential for the regulation of cell polarity and cell fate in the early embryogenesis of many animal species from nematodes to mammals (84, 98). Dvl is an important transducer of divergent Wnt pathways. Nucleoredoxin negatively regulates Wnt--catenin signaling but binds to Dvl, which is in a downstream of the Wnt--catenin signaling, in a redox-dependent manner in Xenopus. It is reported that Wnt--catenin signaling is regulated by oxidative stress independently of extracellular Wnts (26). This implies that redox regulation itself may be essential for the signal transduction of normal embryogenesis.

ROS and Abnormal Embryonic Development

In diabetic environments or hyperglycemia, embryonic dysmorphogenesis may be induced by the generation of ROS (22) and ROS scavenging enzymes can protect diabetic embryos from glucose-induced malformations (21). In rat embryos, hyperglycemia-induced anomalies are associated with glutathione (GSH) depletion and are attenuated by GSH esters (126). GSH is the major system of thiol-disulfide oxidoreduction. The teratogenic effect of diabetic serum was prevented by SOD and N-acetyl-L-cysteine in rat whole embryo culture. These results suggest that embryonic metabolic disorders like diabetes also induce a redox imbalance and the generation of ROS.

Fantel provided evidence that ROS are involved in embryotoxicity and teratogenicity during prenatal life (23). ROS mediate the embryotoxicity and teratogenicity of chemicals such as phenytoin, ethanol, nicotine, and thalidomide.

The anticonvulsant drug phenytoin (dephenylhydantoin) is teratogenic in several animal models, as well as in humans, and produces various malformations including limb defects. These malformations are induced by vascular disruptions that result from embryonic hypoxia, secondarily to hypoperfusion (103, 105). Winn and Wells (135) showed that maternal administration of polyethylene SOD enhances the embryo toxicity of phenytoin, and the antioxidant glycol-catalase can modulate its teratogenicity. This implies that the formation of ROS is associated with phenytoin-related teratogenesis (135).

Excessive alcohol consumption during pregnancy can result in fetal alcohol syndrome, which is characterized by abnormalities in the central nervous system, reduced brain size (microcephaly), growth retardation, and facial dysmorphology in the newborn (124). It has been well established that chronic and excessive ethanol consumption can lead to cell death and tissue damage through the generation of ROS (32). In fact, oxidative stress is one of the many proposed mechanisms that contribute to nervous system dysfunction in fetal alcohol syndrome (12). Peng et al. (95) indicated that ascorbic acid effectively protected ethanol-treated Xenopus embryos from growth retardation and microcephaly and inhibited the ethanol-induced ROS formation and NF-B activation.

Nicotine, which is one of the major products from cigarette smoking, induces mouse embryonic anomalies in culture during the early period of organogenesis stage (mouse E8.5). It is well known that maternal cigarette smoking causes perinatal complications, including low birth weight, preterm delivery, stillbirth, high perinatal mortality, and birth defects in the offspring (33, 40, 52, 109, 130). The abnomalites are mediated by apoptosis induced by an increase in intracellular Ca²⁺ and oxidative stress. The addition of BAPTA-AM, as a Ca²⁺ chelator, or vitamin C, as a ROS scavenger, attenuated these anomalies (143).

Thalidomide, a species-specific teratogen, causes depletion of limbs. There are several hypotheses to explain the mechanism of teratogenesis. Current observations show that thalidomide increases the production of free radicals and elicits oxidative stress (30). Thalidomide shifts the glutathione depletion/oxidation state and intracellular redox potential in limbs of thalidomide-sensitive rabbits but not in resistant rats. NF-B expression is significantly decreased in rabbit limb cells. Therefore, species-specific teratogenicity could be explained by the redox microenvironment caused by free radical production from thalidomide (30).

TRX System and Embryonic Development

It is possible that the TRX family is deeply associated with redox regulation during embryonic development. As mentioned in Oxygen Regulation During Normal Embryonic Development, in culture medium, the addition of TRX or other antioxidative enzymes, SOD, could release mouse embryos from the two-cell block in vitro (82, 83). Removing oxidative stress is important if embryonic development is to continue during in vitro fertilization. TRX is effective against oxidative stress in preimplantational embryos.

Embryos are most vulnerable and sensitive to environmental insult during the early organogenesis period. The TRX system may play an essential role in the acquisition of resistance to oxygen. We showed that TRX overexpressing transgenic embryos are more resistant to high oxygen pressure (25% oxygen) and have significantly less severe abnormalities when cultivated from E7.5 for 48 h (Fig. 2) (57). TRX is expressed in the decidua from E7.5 and in the heart from E8.5 but not from E7.5 in mouse embryo. The TRX knockout mouse is lethal in the early postimplantation period around E7.5 (68). The early embryonic death is associated with a dramatically reduced proliferation of inner mass cells. However, mice lacking other redox regulative enzymes such as Cu/Zn-SOD, Mn-SOD, and glutathione peroxidase-1 have reportedly been born normally. These enzymes may not be essential for embryonic development, or other molecules may compensate for their absence. Therefore, TRX may play a specific role during embryonic development.

View larger version (26K): [in this window] [in a new window]   Fig. 2. Effects of TRX on mouse embryos cultured from embryonic day 7.5 under different oxygen concentrations. Wild-type (WT) and TRX-overexpressed transgenic embryos were cultured under a proper oxygen concentration or high (25%) oxygen concentration for 48 h. The WT and TRX transgenic embryos grew comparably when cultured under the proper oxygen concentration. When exposed to high oxygen concentration, growth was retarded and malformations such as open neural tube, microcephaly, and malrotation of the body axis were induced in WT embryos. The growth of TRX transgenic embryos was significantly better than that of WT embryos.

TRX has another important role as an early pregnancy factor (16). The "early pregnancy factor" was first described in 1976. This phenomenon was revealed in vitro by the rosette inhibition assay, which detects lymphocyte-modifying activity in maternal serum. This factor is detected within hours of fertilization; it is present for at least the first two-thirds of pregnancy, with continued detection dependent on the presence of a viable embryo or fetus (9). Tonissen et al. (123) showed that cysteine-73 residue is essential for the rosette inhibition but not cysteines (32 and 35) at the redox active site in TRX. TRX expression is probably associated with the proliferating and metabolic activities of the cell during embryonic development (56). It is possible that TRX has various roles in not only redox regulation but also embryonic development.

So far, there is no evidence that the teratogens involved in oxidative stress are regulated by the TRX system directly. However, from the previous observations, it is possible that the TRX system controls redox regulation during embryogenesis under both normal and abnormal conditions. Since the mechanism of teratogenesis in some teratogens involves NF-B, it is possible that TRX has a crucial role in teratogenesis.

Oxidative Stress and TRX in Cardiac Diseases

ROS are proposed to contribute to the deterioration of cardiac function in patients with heart disease. It has been reported that ROS are increased in the failing heart and are involved in atherosclerosis, myocardial ischemia-reperfusion injury, and heart failure (115). Previous investigations suggest that TRX and the TRX system have an important role in the cellular defense against oxidative stress in cardiovascular disease. The secretion of TRX into plasma may be a host defense response against oxidative stress. So far, the mechanism by which TRX is secreted into serum is unknown. As mentioned in TRX as a Redox Regulating System, since TRX was cloned as adult T-cell leukemia-derived factor, a cytokine-like factor, evidence has been accumulating that TRX has cytokine-like functions. From a TRX promotor analysis, it is suggested that TRX is induced by inflammatory cytokines such as interferon and IL-6 (50). Exogenous TRX enhances cell growth by itself and shows comitogenicity with other cytokines (4). Circlulating TRX in plasma is almost in the dimer form and does not show any reducing activity. Oxidized TRX as well as reduced TRX shows an anti-inflammatory effect such as inhibition of enutrophil extravasation into the inflammatory site (79).

Oxidative stress is deeply involved in the development of atherosclerotic plaques. Oxidized LDL is phagocytosed by subintimal macrophages that subsequently release numerous inflammatory mediators and enhance atherosclerosis. It is also suggested that inflammation and injury of the vascular endothelium are important for the progression of atherosclerosis. In the early pathogenesis of atherosclerosis, intimal injury enhances the expression of adhesion molecules and promotes the recruitment of monocytes and macrophages. These recruited mononuclear cells are transformed into foamy cells. Prolonged intimal inflammation spreads to arterial media and enhances the proliferation of arterial smooth muscle cells. Leukocytes such as T lymphocytes are recruited, and platelets are agglutinated, making the atherosclerotic plaque unstable (96). The expressions of TRX protein and mRNA are increased in endothelial cells and macrophages in human atherosclerotic plaques but not in nonatherosclerotic lesions (114). In atherosclerotic lesions of autopsy samples of human coronary arteries, it was reported that infiltrating macrophages express high levels of TRX and glutaredoxin (GRX), which catalyze protein disulfide reductions (92). TRX protein and mRNA are also increasingly expressed at injury in the neointimal regenerating endothelial cells of baloon-injured rat arteries (114). Okuda et al. (92) reported that the uptake of oxidized LDL induces the upregulation of glutathione and the TRX system, which may modulate the development of atherosclerosis. Because TRX attenuates inflammatory reactions of human monocyte-derived macrophages and cells (5), it may be involved in atherosclerosis.

Overexpressed TRX transgenic mice survive longer (70) and are more resistant to oxidative stress, such as postischemic-reperfusion injury in the brain (114) and kidney (53), photic injury of the retina (118), and 2,3,7,8-tetrachlorodibenzy-p-dioxin-induced hematotoxicity (141). Therefore, TRX may play a role in preventing oxidative stress in ischemic-reperfusion injury. ROS are also deeply involved in the ongoing ischemia and ischemia-reperfusion in various tissues. ROS are generated primarily from mitochondria within ischemic tissues and secondarily from NADPH oxidases in vascular cells and myocytes, as well as from neutrophils infiltrating the sites of injury and infarction during heart attack and stroke. In the vasculature, ROS interact with nitric oxide, generating the highly reactive peroxinitorite radical, with the dual effect of decreasing the bioavailability of nitric oxide, causing vasoconstriction, and aggravating oxidative damage. ROS initiate damage by directly oxidizing cellular components including proteins, lipids, and DNA, and, secondarily, modulate signaling pathways that influence cell fate. In the reperfused ischemic heart, the high level of oxidative stress is caused by a combination of increased ROS production and decreased antioxidative defense. The initiating stimulus is believed to involve ROS that are produced during reperfusion when electron transport resumes in the mitochondria after suppression by ischemia. Programmed cell death is a significant component of infarction, and there is evidence that multiple pathways are initiated during both the ischemia and reperfusion phases (133). Serum TRX levels are elevated in patients with acute coronary syndrome and dilated cardiomyopathy (108) but not in stable angina patients (55) compared with controls. Kaga et al. (49) reported that treatment with resveratrol, a naturally occuring polyphenol, improved neovascularization in the infarct myocardium, and the effect was mediated by the induction of TRX. It has also been reported that the level of oxidized TRX in plasma is increased during reperfusion of the postcardioplegic heart because of systematic oxidative stress (80).

Myocarditis is an inflammatory injury of the myocardium and is usually caused by a viral infection. The pathology of myocarditis is characterized by inflammatory cell infiltration and necrosis of myocardial cells. Persistent myocardial injury causes tissue remodeling and occasionally leads to myocardial dysfunction or cardiomyopathy (25, 94). Oxidative stress is involved in the pathogenesis of myocarditis since antioxidants have a beneficial effect against viral myocarditis (34, 35). It was reported that the serum level of TRX was high during the acute phase, then slowly decreased during the chronic phase, in a patient with fulminant myocarditis (106). It is suggested that TRX may be induced by acute inflammatory stimuli and serve as a regulator of the immunoresponse. Acute myocarditis is a potentially lethal disease and frequently precedes the development of dilated cardiomyopathy. During acute inflammatory myocarditis, as TRX is upregulated concomitant with NF-B upregulation, TRX may play a protective role against the progressive myocardial damage to cardiomyocytes (107). It was also reported that the expression of TRX was increased in inflammatory cells and cardiomyocytes of left ventricular biopsy samples in a patient with fulmimant myocarditis (106). It is also reported that circulating TRX inhibited the neutrophil recruitment to the inflammatory sites in a mouse air pouch model (79). It is feasible that the TRX elevation in patients with myocarditis is associated with not only the host defense response against oxidative stress but also inhibition of the neutrophil recruitment into myocardial lesions. Cardiovascular drugs such as temocapril have cytoprotective effects through the upregulation of TRX in cardiomyocytes (142). Temocapril is a nonsulfhydryl-containing angiotensin-converting enzyme inhibitor and enhances the protein expression of TRX but not TRX-2, Cu/Zn- SOD, or Mn-SOD in the myocardium of rats (142). Temocapril treatment ameliorates the severity of disease in rats with experimental autoimmune myocarditis with reduction of protein oxidation by upregulated TRX in a preconditioning manner. Overexpression of TRX in TRX-TG mice had a protective effect on postischemic reperfusion injury in the brain (41, 114). It is also reported that endogenous TRX has an essential role in protection against ischemia in the heart (128). Depletion of TRX abolished this cardioprotection by reducing postischemic ventricular recovery, promoting myocardial infarction and cardiomyocyte apoptosis.

Cardiomyopathy is a cardiac dysfunction caused by myocardial injury. Oxidative stress has been implicated in the onset and progression of diabetes-associated heart dysfunction (diabetic cardiomyopathy) (136). Li et al. (64) suggested that decreased glucose metabolism is a key factor underlying changes in K⁺ channel function in myocytes from rats with streptozotocin-induced diabetes. The consequences of diabetes-related hyperglycemia and impaired glucose metabolism for cardiac K⁺ channel function involve alterations in the cell redox state (99, 138). In a diabetic cardiomyopathy rat model, Li et al. (64) reported that redox-sensitive K⁺ channels, regulated by the TRX system, and TRXR activity and GRX reductase were significantly suppressed. On the other hand, TRX and GRX activities were increased. Cardiac TRX and GRX systems comprise a functionally important repair mechanism that protects ion channels and associated cellular proteins from irreversible oxidative damage (64).

In the rat model, adriamycin (Adr) induces cardiomyopathy in a dose-dependent manner. Adr is an important anticancer drug widely used in the treatment of tumors. However, its use is limited by a potentially lethal and dose-dependent congestive cardiomyopathy (110). Adr-induced cardiotoxicity has been attributed, at least in part, to ROS-mediated damage of cardiomyocytes (20, 122). TRX expression correlates with the resistance to Adr in T-cell leukemia cell lines (131). In Adr-treated neonatal rat cardiomyocytes, TRX was increased dose dependently, concomitant with the formation of hydroxyl radicals and oxidized proteins in the damaged cardiomyocytes (106). However, the expression of Cu/Zn-SOD nor Mn-SOD was changed by Adr treatment. TRX has a protective role against Adr-induced cardiotoxicity by reducing oxidative stress. Shioji et al. (106) suggested that TRX-TG mice are more resistant to Adr-induced cardiotoxicity than wild-type (WT) mice. The formation of hydroxyl radicals was decreased, and ultrastructural morphology was better maintained. All WT mice treated with 24 mg/kg of Adr died within 6 wk, but five of six TRX-TG mice survived much longer under the same conditions. It was also reported that high-dose recombinant TRX treatment reduced Adr-induced injury in neonatal rat cardiomyocytes in vitro. The differences in viability between WT and TRX-TG mice treated with Adr depended on the dose of TRX. It was suggested that TRX and the redox system modulated by TRX have important roles in the cellular defense against oxidative stress in cardiomyocytes. In embryonic mice, the TRX2 knockout mice were lethal (89). However, in the heart, TRX2 protein is not upregulated in acute myocarditis or Adr-induced cardiotoxicity (108).

Wang et al. (132) reported that biochemical strain or hydrogen peroxide suppressed the expression of TBP-2 protein and mRNA in rat primary cardiomyocytes. Overexpresson of TBP-2 induced apoptosis, suggesting that TBP-2 acts as an environmental stress-mediated regulator of cardiomyocyte viability. In another investigation, overexpression of TBP-2 blocksed platelet-derived growth factor-induced cell growth through the suppression of TRX activity in human aortic smooth muscle cells (104).

TRX as a Biomarker of Oxidative Stress

TRX is secreted from the response of cells to oxidative stress. The measurement of serum TRX may be a good tool to detect oxidative stress (Table 1). Miyamoto et al. (74) found that serum plasminogen activator inhibitor levels and serum TRX levels were both elevated in patients with vasospastic angina, and treatment with vitamin E, an antioxidant, decreased the two indexes (74). Plasma TRX levels are elevated in patients with unstable angina and acute myocardial infarction compared with those with stable exertional angina and chest pain syndrome (37, 111). Elevated TRX levels in the plasma of patients with myocardial infarction are associated with platelet hyperaggregability, which is a part of the pathogenesis of ischemic heart disease (75). Plasma TRX levels and aggregability increased concomitantly in patients with acute myocarditis infarction. The increase in plasma TRX levels was associated with platelet hyperaggregability and a lower left ventricular ejection fraction. They also suggested a negative correlation between oxidative stress and fibrinolytic activity, a defense mechanism against thrombus formation that augments the narrowing of the constricted coronary artery (73). Tsujita et al. (127) reported that the administration of edaravone, a free radical scavenger, before the reperfusion of hearts with myocardial infarction, decreased the serum TRX level along with infarct size, reperfusion arrhythmia, and increased the cumulative event-free rate.

Miwa et al. (72) suggested that serum TRX levels are increased in patients who have one or multiple coronary risk factors (72). Smoking is a major risk factor for coronary spasms and hypertension. Hypercholesterolemia is another coronary risk factor. Serum TRX levels are increased in patients who have one or multiple risk factors and do not seen to differ with the number of risk factors. Serum -tocopherol (vitamine E, antioxidant) levels were also measured in the same patients. Serum -tocopherol levels were increased in patients with one risk factor but lower in the patients with multiple risk factors.

Conclusion

We discussed the importance of redox regulation and the TRX system throughout life from early embryogenesis. As proper oxygen concentration is gradually increased during early embryogenesis until the formation of the placenta, redox regulation is crucial and TRX may play an essential role in the mechanism. However, how this mechanism is established in the early embryonic period is unclear. On the other hand, a redox imbalance produces an excess of ROS and causes various disorders in the various tissues. The TRX system has an important role against oxidative stress in cardiovascular disease. These findings suggest that the serum TRX level is a good candidate for a biomarker of oxidative stress in various cardiovascular diseases. The analysis of redox regulation in biological responses will contribute to the development of new therapeutic approaches for cardiovascular disease.

There is no direct evidence to indicate a correlation between oxygen sensing during early development and cardiovascular disease. The mechanism of oxygen sensing during early development is little understood. However, a further clarification of the mechanism may provide a new insight for studies of oxidative stress and redox regulation in the cardiovascular system.

	GRANTS

TOP ABSTRACT GRANTS REFERENCES

 
This study was supported by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation and a grant for Child Health and Development (18C-3) from the Ministry of Health, Labour, and Welfare.

	ACKNOWLEDGMENTS

 
We thank Prof. Kohei Shiota, Dr. Takashi Miura, Dr. Yoshiyuki Matsuo, Chisayo Kubo, and Megumi Hasegawa.

	FOOTNOTES

 

Address for reprint requests and other correspondence: M. Kobayashi-Miura, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 6068507, Japan (e-mail: mmiura{at}virus.kyoto-u.ac.jp)

	REFERENCES

TOP ABSTRACT GRANTS REFERENCES

 

1. Archer S, Michelakis E. The mechanism(s) of hypoxic pulmonary vasoconstriction: potassium channels, redox O₂ sensors, and controversies. News Physiol Sci 17: 131–137, 2002.[Abstract/Free Full Text]
2. Archer SL, Michelakis ED, Thebaud B, Bonnet S, Moudgil R, Wu XC, Weir EK. A central role for oxygen-sensitive K⁺ channels and mitochondria in the specialized oxygen-sensing system. Novartis Found Symp 272: 157–171, 2006.[Medline]
3. Archer SL, Souil E, Dinh-Xuan AT, Schremmer B, Mercier JC, El Yaagoubi A, Nguyen-Huu L, Reeve HL, Hampl V. Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv21, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes. J Clin Invest 101: 2319–2330, 1998.[Web of Science][Medline]
4. Bertini R, Howard OM, Dong HF, Oppenheim JJ, Bizzarri C, Sergi R, Caselli G, Pagliei S, Romines B, Wilshire JA, Mengozzi M, Nakamura H, Yodoi J, Pekkari K, Gurunath R, Holmgren A, Herzenberg LA, Ghezzi P. Thioredoxin, a redox enzyme released in infection and inflammation, is a unique chemoattractant for neutrophils, monocytes, and T cells. J Exp Med 189: 1783–1789, 1999.[Abstract/Free Full Text]
5. Billiet L, Furman C, Larigauderie G, Copin C, Brand K, Fruchart JC, Rouis M. Extracellular human thioredoxin-1 inhibits lipopolysaccharide-induced interleukin-1beta expression in human monocyte-derived macrophages. J Biol Chem 280: 40310–40318, 2005.[Abstract/Free Full Text]
6. Callister ME, Burke-Gaffney A, Quinlan GJ, Nicholson AG, Florio R, Nakamura H, Yodoi J, Evans TW. Extracellular thioredoxin levels are increased in patients with acute lung injury. Thorax 61: 521–527, 2006.[Abstract/Free Full Text]
7. Chen EY, Fujinaga M, Giaccia AJ. Hypoxic microenvironment within an embryo induces apoptosis and is essential for proper morphological development. Teratology 60: 215–225, 1999.[CrossRef][Web of Science][Medline]
8. Cho T, Chan W, Cutz E. Distribution and frequency of neuro-epithelial bodies in post-natal rabbit lung: quantitative study with monoclonal antibody against serotonin. Cell Tissue Res 255: 353–362, 1989.[Web of Science][Medline]
9. Clarke FM. Identification of molecules and mechanisms involved in the 'early pregnancy factor’ system. Reprod Fertil Dev 4: 423–433, 1992.[CrossRef][Medline]
10. Clissold PM, Bicknell R. The thioredoxin-like fold: hidden domains in protein disulfide isomerases and other chaperone proteins. Bioessays 25: 603–611, 2003.[CrossRef][Web of Science][Medline]
12. Cohen-Kerem R, Koren G. Antioxidants and fetal protection against ethanol teratogenicity. I. Review of the experimental data and implications to humans. Neurotoxicol Teratol 25: 1–9, 2003.[CrossRef][Web of Science][Medline]
13. Conrad M, Jakupoglu C, Moreno SG, Lippl S, Banjac A, Schneider M, Beck H, Hatzopoulos AK, Just U, Sinowatz F, Schmahl W, Chien KR, Wurst W, Bornkamm GW, Brielmeier M. Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function. Mol Cell Biol 24: 9414–9423, 2004.[Abstract/Free Full Text]
13. Copp AJ, Cockfort DL. Dissection and Culture of Postimplantation Embryos. New York: Oxford University Press, 1990.
14. Cutz E, Ma TK, Perrin DG, Moore AM, Becker LE. Peripheral chemoreceptors in congenital central hypoventilation syndrome. Am J Respir Crit Care Med 155: 358–363, 1997.[Abstract]
15. Cutz E, Speirs V, Yeger H, Newman C, Wang D, Perrin DG. Cell biology of pulmonary neuroepithelial bodies—validation of an in vitro model. I. Effects of hypoxia and Ca²⁺ ionophore on serotonin content and exocytosis of dense core vesicles. Anat Rec 236: 41–52, 1993.[CrossRef][Medline]
16. Di Trapani G, Orosco C, Perkins A, Clarke F. Isolation from human placental extracts of a preparation possessing ‘early pregnancy factor’ activity and identification of the polypeptide components. Hum Reprod 6: 450–457, 1991.[Abstract/Free Full Text]
17. Dipp M, Nye PC, Evans AM. Hypoxic release of calcium from the sarcoplasmic reticulum of pulmonary artery smooth muscle. Am J Physiol Lung Cell Mol Physiol 281: L318–L325, 2001.[Abstract/Free Full Text]
18. Dirnagl U, Lindauer U, Them A, Schreiber S, Pfister HW, Koedel U, Reszka R, Freyer D, Villringer A. Global cerebral ischemia in the rat: online monitoring of oxygen free radical production using chemiluminescence in vivo. J Cereb Blood Flow Metab 15: 929–940, 1995.[Web of Science][Medline]
19. Dobashi K, Ghosh B, Orak JK, Singh I, Singh AK. Kidney ischemia-reperfusion: modulation of antioxidant defenses. Mol Cell Biochem 205: 1–11, 2000.[CrossRef][Web of Science][Medline]
20. Doroshow JH. Effect of anthracycline antibiotics on oxygen radical formation in rat heart. Cancer Res 43: 460–472, 1983.[Abstract/Free Full Text]
21. Eriksson UJ, Borg LA. Protection by free oxygen radical scavenging enzymes against glucose-induced embryonic malformations in vitro. Diabetologia 34: 325–331, 1991.[CrossRef][Web of Science][Medline]
22. Eriksson UJ, Borg LA, Forsberg H, Styrud J. Diabetic embryopathy. Studies with animal and in vitro models. Diabetes 40, Suppl 2: 94–98, 1991.[Web of Science][Medline]
23. Fantel AG. Reactive oxygen species in developmental toxicity: review and hypothesis. Teratology 53: 196–217, 1996.[CrossRef][Web of Science][Medline]
24. Fu XW, Wang D, Nurse CA, Dinauer MC, Cutz E. NADPH oxidase is an O₂ sensor in airway chemoreceptors: evidence from K⁺ current modulation in wild-type and oxidase-deficient mice. Proc Natl Acad Sci USA 97: 4374–4379, 2000.[Abstract/Free Full Text]
25. Fujioka S, Kitaura Y, Ukimura A, Deguchi H, Kawamura K, Isomura T, Suma H, Shimizu A. Evaluation of viral infection in the myocardium of patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 36: 1920–1926, 2000.[Abstract/Free Full Text]
26. Funato Y, Michiue T, Asashima M, Miki H. The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-beta-catenin signalling through dishevelled. Nat Cell Biol 8: 501–508, 2006.[CrossRef][Web of Science][Medline]
27. Fuster V, Stein B, Ambrose JA, Badimon L, Badimon JJ, Chesebro JH. Atherosclerotic plaque rupture and thrombosis. Evolving concepts. Circulation 82: II47–II59, 1990.[Medline]
28. Gupta M, Dobashi K, Greene EL, Orak JK, Singh I. Studies on hepatic injury and antioxidant enzyme activities in rat subcellular organelles following in vivo ischemia and reperfusion. Mol Cell Biochem 176: 337–347, 1997.[CrossRef][Web of Science][Medline]
29. Hampl V, Bibova J, Stranak Z, Wu X, Michelakis ED, Hashimoto K, Archer SL. Hypoxic fetoplacental vasoconstriction in humans is mediated by potassium channel inhibition. Am J Physiol Heart Circ Physiol 283: H2440–H2449, 2002.[Abstract/Free Full Text]
30. Hansen JM, Harris C. A novel hypothesis for thalidomide-induced limb teratogenesis: redox misregulation of the NF-kappaB pathway. Antioxid Redox Signal 6: 1–14, 2004.[CrossRef][Web of Science][Medline]
31. Hashimoto S, Matsumoto K, Gon Y, Furuichi S, Maruoka S, Takeshita I, Hirota K, Yodoi J, Horie T. Thioredoxin negatively regulates p38 MAP kinase activation and IL-6 production by tumor necrosis factor-alpha. Biochem Biophys Res Commun 258: 443–447, 1999.[CrossRef][Web of Science][Medline]
32. Henderson GI, Chen JJ, Schenker S. Ethanol, oxidative stress, reactive aldehydes, and the fetus. Front Biosci 4: D541–D550, 1999.[Medline]
33. Himmelberger DU, Brown BW Jr, Cohen EN. Cigarette smoking during pregnancy and the occurrence of spontaneous abortion and congenital abnormality. Am J Epidemiol 108: 470–479, 1978.[Abstract/Free Full Text]
34. Hiraoka Y, Kishimoto C, Kurokawa M, Ochiai H, Sasayama S. Effects of polyethylene glycol conjugated superoxide dismutase on coxsackievirus B3 myocarditis in mice. Cardiovasc Res 26: 956–961, 1992.[Abstract/Free Full Text]
35. Hiraoka Y, Kishimoto C, Takada H, Kurokawa M, Ochiai H, Shiraki K, Sasayama S. Role of oxygen derived free radicals in the pathogenesis of coxsackievirus B3 myocarditis in mice. Cardiovasc Res 27: 957–961, 1993.[Free Full Text]
36. Hirota K, Matsui M, Iwata S, Nishiyama A, Mori K, Yodoi J. AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Proc Natl Acad Sci USA 94: 3633–3638, 1997.[Abstract/Free Full Text]
37. Hokamaki J, Kawano H, Soejima H, Miyamoto S, Kajiwara I, Kojima S, Sakamoto T, Sugiyama S, Yoshimura M, Nakamura H, Yodoi J, Ogawa H. Plasma thioredoxin levels in patients with unstable angina. Int J Cardiol 99: 225–231, 2005.[CrossRef][Web of Science][Medline]
38. Holmgren A. Antioxidant function of thioredoxin and glutaredoxin systems. Antioxid Redox Signal 2: 811–820, 2000.[Medline]
39. Holmgren A, Buchanan BB, Wolosiuk RA. Photosynthetic regulatory protein from rabbit liver is identical with thioredoxin. FEBS Lett 82: 351–354, 1977.[CrossRef][Web of Science][Medline]
40. Horta BL, Victora CG, Menezes AM, Halpern R, Barros FC. Low birthweight, preterm births and intrauterine growth retardation in relation to maternal smoking. Paediatr Perinat Epidemiol 11: 140–151, 1997.[CrossRef][Web of Science][Medline]
41. Hotta M, Tashiro F, Ikegami H, Niwa H, Ogihara T, Yodoi J, Miyazaki J. Pancreatic beta cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and streptozotocin-induced diabetes. J Exp Med 188: 1445–1451, 1998.[Abstract/Free Full Text]
42. Howard RB, Hosokawa T, Maguire MH. Hypoxia-induced fetoplacental vasoconstriction in perfused human placental cotyledons. Am J Obstet Gynecol 157: 1261–1266, 1987.[Web of Science][Medline]
43. Huang LE, Arany Z, Livingston DM, Bunn HF. Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem 271: 32253–32259, 1996.[Abstract/Free Full Text]
44. Jakupoglu C, Przemeck GK, Schneider M, Moreno SG, Mayr N, Hatzopoulos AK, de Angelis MH, Wurst W, Bornkamm GW, Brielmeier M, Conrad M. Cytoplasmic thioredoxin reductase is essential for embryogenesis but dispensable for cardiac development. Mol Cell Biol 25: 1980–1988, 2005.[Abstract/Free Full Text]
45. Jekell A, Hossain A, Alehagen U, Dahlstrom U, Rosen A. Elevated circulating levels of thioredoxin and stress in chronic heart failure. Eur J Heart Fail 6: 883–890, 2004.[Web of Science][Medline]
46. Jikimoto T, Nishikubo Y, Koshiba M, Kanagawa S, Morinobu S, Morinobu A, Saura R, Mizuno K, Kondo S, Toyokuni S, Nakamura H, Yodoi J, Kumagai S. Thioredoxin as a biomarker for oxidative stress in patients with rheumatoid arthritis. Mol Immunol 38: 765–772, 2002.[CrossRef][Web of Science][Medline]
47. Johnson MH, Nasr-Esfahani MH. Radical solutions and cultural problems: could free oxygen radicals be responsible for the impaired development of preimplantation mammalian embryos in vitro? Bioessays 16: 31–38, 1994.[CrossRef][Web of Science][Medline]
48. Junn E, Han SH, Im JY, Yang Y, Cho EW, Um HD, Kim DK, Lee KW, Han PL, Rhee SG, Choi I. Vitamin D₃ up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J Immunol 164: 6287–6295, 2000.[Abstract/Free Full Text]
49. Kaga S, Zhan L, Matsumoto M, Maulik N. Resveratrol enhances neovascularization in the infarcted rat myocardium through the induction of thioredoxin-1, heme oxygenase-1 and vascular endothelial growth factor. J Mol Cell Cardiol 39: 813–822, 2005.[CrossRef][Web of Science][Medline]
50. Kaghad M, Dessarps F, Jacquemin-Sablon H, Caput D, Fradelizi D, Wollman EE. Genomic cloning of human thioredoxin-encoding gene: mapping of the transcription start point and analysis of the promoter. Gene 140: 273–278, 1994.[CrossRef][Web of Science][Medline]
51. Kakisaka Y, Nakashima T, Sumida Y, Yoh T, Nakamura H, Yodoi J, Senmaru H. Elevation of serum thioredoxin levels in patients with Type 2 diabetes. Horm Metab Res 34: 160–164, 2002.[Web of Science][Medline]
52. Kallen K. Maternal smoking during pregnancy and infant head circumference at birth. Early Hum Dev 58: 197–204, 2000.[CrossRef][Web of Science][Medline]
53. Kasuno K, Nakamura H, Ono T, Muso E, Yodoi J. Protective roles of thioredoxin, a redox-regulating protein, in renal ischemia/reperfusion injury. Kidney Int 64: 1273–1282, 2003.[CrossRef][Web of Science][Medline]
54. Kishimoto C, Shioji K, Kinoshita M, Iwase T, Tamaki S, Fujii M, Murashige A, Maruhashi H, Takeda S, Nonogi H, Hashimoto T. Treatment of acute inflammatory cardiomyopathy with intravenous immunoglobulin ameliorates left ventricular function associated with suppression of inflammatory cytokines and decreased oxidative stress. Int J Cardiol 91: 173–178, 2003.[CrossRef][Web of Science][Medline]
55. Kishimoto C, Shioji K, Nakamura H, Nakayama Y, Yodoi J, Sasayama S. Serum thioredoxin (TRX) levels in patients with heart failure. Jpn Circ J 65: 491–494, 2001.[CrossRef][Medline]
56. Kobayashi M, Nakamura H, Yodoi J, Shiota K. Immunohistochemical localization of thioredoxin and glutaredoxin in mouse embryos and fetuses. Antioxid Redox Signal 2: 653–663, 2000.[Medline]
57. Kobayashi-Miura M, Nakamura H, Yodoi J, Shiota K. Thioredoxin, an anti-oxidant protein, protects mouse embryos from oxidative stress-induced developmental anomalies. Free Radic Res 36: 949–956, 2002.[CrossRef][Web of Science][Medline]
58. Lambers DS, Clark KE. The maternal and fetal physiologic effects of nicotine. Semin Perinatol 20: 115–126, 1996.[CrossRef][Web of Science][Medline]
59. Laurent TC, Moore EC, Reichard P. Enzymatic synthesis of deoxyribonucleotides. IV. Isolation and characterization of thioredoxin, the hydrogen donor from Escherichia coli B. J Biol Chem 239: 3436–3444, 1964.[Free Full Text]
60. Lauweryns JM, Cokelaere M, Deleersynder M, Liebens M. Intrapulmonary neuro-epithelial bodies in newborn rabbits. Influence of hypoxia, hyperoxia, hypercapnia, nicotine, reserpine, L-DOPA and 5-HTP. Cell Tissue Res 182: 425–440, 1977.[Web of Science][Medline]
61. Lauweryns JM, Peuskens JC. Neuro-epithelial bodies (neuroreceptor or secretory organs?) in human infant bronchial and bronchiolar epithelium. Anat Rec 172: 471–481, 1972.[CrossRef][Medline]
62. Lefer DJ, Granger DN. Oxidative stress and cardiac disease. Am J Med 109: 315–323, 2000.[CrossRef][Web of Science][Medline]
63. Legge M, Sellens MH. Free radical scavengers ameliorate the 2-cell block in mouse embryo culture. Hum Reprod 6: 867–871, 1991.[Abstract/Free Full Text]
64. Li X, Xu Z, Li S, Rozanski GJ. Redox regulation of I_to remodeling in diabetic rat heart. Am J Physiol Heart Circ Physiol 288: H1417–H1424, 2005.[Abstract/Free Full Text]
65. Libby P. Molecular bases of the acute coronary syndromes. Circulation 91: 2844–2850, 1995.[Free Full Text]
66. Lopez-Barneo J, Pardal R, Montoro RJ, Smani T, Garcia-Hirschfeld J, Urena J. K⁺ and Ca²⁺ channel activity and cytosolic [Ca²⁺] in oxygen-sensing tissues. Respir Physiol 115: 215–227, 1999.[CrossRef][Web of Science][Medline]
67. Lopez-Barneo J, Pardal R, Ortega-Saenz P. Cellular mechanism of oxygen sensing. Annu Rev Physiol 63: 259–287, 2001.[CrossRef][Web of Science][Medline]
68. Matsui M, Oshima M, Oshima H, Takaku K, Maruyama T, Yodoi J, Taketo MM. Early embryonic lethality caused by targeted disruption of the mouse thioredoxin gene. Dev Biol 178: 179–185, 1996.[CrossRef][Web of Science][Medline]
69. Michelakis ED, Archer SL, Weir EK. Acute hypoxic pulmonary vasoconstriction: a model of oxygen sensing. Physiol Res 44: 361–367, 1995.[Web of Science][Medline]
70. Mitsui A, Hamuro J, Nakamura H, Kondo N, Hirabayashi Y, Ishizaki-Koizumi S, Hirakawa T, Inoue T, Yodoi J. Overexpression of human thioredoxin in transgenic mice controls oxidative stress and life span. Antioxid Redox Signal 4: 693–696, 2002.[CrossRef][Web of Science][Medline]
71. Miwa K, Kishimoto C, Nakamura H, Makita T, Ishii K, Okuda N, Taniguchi A, Shioji K, Yodoi J, Sasayama S. Increased oxidative stress with elevated serum thioredoxin level in patients with coronary spastic angina. Clin Cardiol 26: 177–181, 2003.[Web of Science][Medline]
72. Miwa K, Kishimoto C, Nakamura H, Makita T, Ishii K, Okuda N, Yodoi J, Sasayama S. Serum thioredoxin and alpha-tocopherol concentrations in patients with major risk factors. Circ J 69: 291–294, 2005.[CrossRef][Web of Science][Medline]
73. Miyamoto S, Kawano H, Sakamoto T, Soejima H, Kajiwara I, Hokamaki J, Hirai N, Sugiyama S, Yoshimura M, Yasue H, Nakamura H, Yodoi J, Ogawa H. Increased plasma levels of thioredoxin in patients with coronary spastic angina. Antioxid Redox Signal 6: 75–80, 2004.[CrossRef][Web of Science][Medline]
74. Miyamoto S, Kawano H, Takazoe K, Soejima H, Sakamoto T, Hokamaki J, Yoshimura M, Nakamura H, Yodoi J, Ogawa H. Vitamin E improves fibrinolytic activity in patients with coronary spastic angina. Thromb Res 113: 345–351, 2004.[CrossRef][Web of Science][Medline]
75. Miyamoto S, Sakamoto T, Soejima H, Shimomura H, Kajiwara I, Kojima S, Hokamaki J, Sugiyama S, Yoshimura M, Ozaki Y, Nakamura H, Yodoi J, Ogawa H. Plasma thioredoxin levels and platelet aggregability in patients with acute myocardial infarction. Am Heart J 146: 465–471, 2003.[CrossRef][Web of Science][Medline]
76. Morriss GM, New DA. Effect of oxygen concentration on morphogenesis of cranial neural folds and neural crest in cultured rat embryos. J Embryol Exp Morphol 54: 17–35, 1979.[Web of Science][Medline]
77. Nakamura H, De Rosa S, Roederer M, Anderson MT, Dubs JG, Yodoi J, Holmgren A, Herzenberg LA, Herzenberg LA. Elevation of plasma thioredoxin levels in HIV-infected individuals. Int Immunol 8: 603–611, 1996.[Abstract/Free Full Text]
78. Nakamura H, De Rosa SC, Yodoi J, Holmgren A, Ghezzi P, Herzenberg LA, Herzenberg LA. Chronic elevation of plasma thioredoxin: inhibition of chemotaxis and curtailment of life expectancy in AIDS. Proc Natl Acad Sci USA 98: 2688–2693, 2001.[Abstract/Free Full Text]
79. Nakamura H, Herzenberg LA, Bai J, Araya S, Kondo N, Nishinaka Y, Herzenberg LA, Yodoi J. Circulating thioredoxin suppresses lipopolysaccharide-induced neutrophil chemotaxis. Proc Natl Acad Sci USA 98: 15143–15148, 2001.[Abstract/Free Full Text]
80. Nakamura H, Matsuda M, Furuke K, Kitaoka Y, Iwata S, Toda K, Inamoto T, Yamaoka Y, Ozawa K, Yodoi J. Adult T cell leukemia-derived factor/human thioredoxin protects endothelial F-2 cell injury caused by activated neutrophils or hydrogen peroxide. Immunol Lett 42: 75–80, 1994.[CrossRef][Web of Science][Medline]
81. Nakamura H, Nakamura K, Yodoi J. Redox regulation of cellular activation. Annu Rev Immunol 15: 351–369, 1997.[CrossRef][Web of Science][Medline]
82. Natsuyama S, Noda Y, Narimoto K, Umaoka Y, Mori T. Release of two-cell block by reduction of protein disulfide with thioredoxin from Escherichia coli in mice. J Reprod Fertil 95: 649–656, 1992.[Abstract/Free Full Text]
83. Natsuyama S, Noda Y, Yamashita M, Nagahama Y, Mori T. Superoxide dismutase and thioredoxin restore defective p34cdc2 kinase activation in mouse two-cell block. Biochim Biophys Acta 1176: 90–94, 1993.[Medline]
84. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 303: 1483–1487, 2004.[Abstract/Free Full Text]
85. New DA, Coppola PT. Effects of different oxygen concentrations on the development of rat embryos in culture. J Reprod Fertil 21: 109–118, 1970.[Abstract/Free Full Text]
86. New DA, Coppola PT, Cockroft DL. Comparison of growth in vitro and in vivo of post-implantation rat embryos. J Embryol Exp Morphol 36: 133–144, 1976.[Web of Science][Medline]
87. Nishiyama A, Matsui M, Iwata S, Hirota K, Masutani H, Nakamura H, Takagi Y, Sono H, Gon Y, Yodoi J. Identification of thioredoxin-binding protein-2/vitamin D₃ up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J Biol Chem 274: 21645–21650, 1999.[Abstract/Free Full Text]
88. Nishiyama A, Ohno T, Iwata S, Matsui M, Hirota K, Masutani H, Nakamura H, Yodoi J. Demonstration of the interaction of thioredoxin with p40phox, a phagocyte oxidase component, using a yeast two-hybrid system. Immunol Lett 68: 155–159, 1999.[CrossRef][Web of Science][Medline]
89. Nonn L, Williams RR, Erickson RP, Powis G. The absence of mitochondrial thioredoxin 2 causes massive apoptosis, exencephaly, and early embryonic lethality in homozygous mice. Mol Cell Biol 23: 916–922, 2003.[Abstract/Free Full Text]
90. Nurse CA, Buttigieg J, Thompson R, Zhang M, Cutz E. Oxygen sensing in neuroepithelial and adrenal chromaffin cells. Novartis Found Symp 272: 106–114, 2006.[Medline]
91. Okamoto T, Ogiwara H, Hayashi T, Mitsui A, Kawabe T, Yodoi J. Human thioredoxin/adult T cell leukemia-derived factor activates the enhancer binding protein of human immunodeficiency virus type 1 by thiol redox control mechanism. Int Immunol 4: 811–819, 1992.[Abstract/Free Full Text]
92. Okuda M, Inoue N, Azumi H, Seno T, Sumi Y, Hirata K, Kawashima S, Hayashi Y, Itoh H, Yodoi J, Yokoyama M. Expression of glutaredoxin in human coronary arteries: its potential role in antioxidant protection against atherosclerosis. Arterioscler Thromb Vasc Biol 21: 1483–1487, 2001.[Abstract/Free Full Text]
93. Parman T, Wiley MJ, Wells PG. Free radical-mediated oxidative DNA damage in the mechanism of thalidomide teratogenicity. Nat Med 5: 582–585, 1999.[CrossRef][Web of Science][Medline]
94. Pauschinger M, Bowles NE, Fuentes-Garcia FJ, Pham V, Kuhl U, Schwimmbeck PL, Schultheiss HP, Towbin JA. Detection of adenoviral genome in the myocardium of adult patients with idiopathic left ventricular dysfunction. Circulation 99: 1348–1354, 1999.[Abstract/Free Full Text]
95. Peng Y, Kwok KH, Yang PH, Ng SS, Liu J, Wong OG, He ML, Kung HF, Lin MC. Ascorbic acid inhibits ROS production, NF-kappa B activation and prevents ethanol-induced growth retardation and microencephaly. Neuropharmacology 48: 426–434, 2005.[CrossRef][Web of Science][Medline]
96. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest 98: 2572–2579, 1996.[Web of Science][Medline]
97. Reeve HL, Weir EK, Nelson DP, Peterson DA, Archer SL. Opposing effects of oxidants and antioxidants on K⁺ channel activity and tone in rat vascular tissue. Exp Physiol 80: 825–834, 1995.[Abstract]
98. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature 434: 843–850, 2005.[CrossRef][Medline]
99. Rozanski GJ, Xu Z. A metabolic mechanism for cardiac K⁺ channel remodelling. Clin Exp Pharmacol Physiol 29: 132–137, 2002.[CrossRef][Web of Science][Medline]
100. Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J 17: 2596–2606, 1998.[CrossRef][Web of Science][Medline]
101. Salas-Vidal E, Lomeli H, Castro-Obregon S, Cuervo R, Escalante-Alcalde D, Covarrubias L. Reactive oxygen species participate in the control of mouse embryonic cell death. Exp Cell Res 238: 136–147, 1998.[CrossRef][Web of Science][Medline]
102. Sato N, Iwata S, Nakamura K, Hori T, Mori K, Yodoi J. Thiol-mediated redox regulation of apoptosis. Possible roles of cellular thiols other than glutathione in T cell apoptosis. J Immunol 154: 3194–3203, 1995.[Abstract]
103. Schardein J. Chemically Induced Birth Defects. New York: Marcel Dekker, 2000.
104. Schulze PC, De Keulenaer GW, Yoshioka J, Kassik KA, Lee RT. Vitamin D₃-upregulated protein-1 (VDUP-1) regulates redox-dependent vascular smooth muscle cell proliferation through interaction with thioredoxin. Circ Res 91: 689–695, 2002.[Abstract/Free Full Text]
105. Shepard TH. Catalog of Teratogenic Agents. Baltimore, MD: Johns Hopkins University Press, 1998.
106. Shioji K, Kishimoto C, Nakamura H, Masutani H, Yuan Z, Oka S, Yodoi J. Overexpression of thioredoxin-1 in transgenic mice attenuates adriamycin-induced cardiotoxicity. Circulation 106: 1403–1409, 2002.[Abstract/Free Full Text]
107. Shioji K, Kishimoto C, Nakamura H, Toyokuni S, Nakayama Y, Yodoi J, Sasayama S. Upregulation of thioredoxin (TRX) expression in giant cell myocarditis in rats. FEBS Lett 472: 109–113, 2000.[CrossRef][Web of Science][Medline]
108. Shioji K, Nakamura H, Masutani H, Yodoi J. Redox regulation by thioredoxin in cardiovascular diseases. Antioxid Redox Signal 5: 795–802, 2003.[CrossRef][Web of Science][Medline]
109. Shiono PH, Klebanoff MA, Berendes HW. Congenital malformations and maternal smoking during pregnancy. Teratology 34: 65–71, 1986.[CrossRef][Web of Science][Medline]
110. Singal PK, Khaper N, Palace V, Kumar D. The role of oxidative stress in the genesis of heart disease. Cardiovasc Res 40: 426–432, 1998.[Abstract/Free Full Text]
111. Soejima H, Suefuji H, Miyamoto S, Kajiwaram I, Kojima S, Hokamaki J, Sakamoto T, Yoshimura M, Nakamura H, Yodoi J, Ogawa H. Increased plasma thioredoxin in patients with acute myocardial infarction. Clin Cardiol 26: 583–587, 2003.[Web of Science][Medline]
112. Sumida Y, Nakashima T, Yoh T, Furutani M, Hirohama A, Kakisaka Y, Nakajima Y, Ishikawa H, Mitsuyoshi H, Okanoue T, Kashima K, Nakamura H, Yodoi J. Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease. J Hepatol 38: 32–38, 2003.[Web of Science][Medline]
113. Tagaya Y, Maeda Y, Mitsui A, Kando N, Matsui H, Hamuro J, Brown N, Arai K, Yokota T, Wakasugi H, Yodoi J. ATL-derived factor (ADF), an IL-2 receptor/Tac inducer homologous to thioredoxin; possible involvement of dithiol-reduction in the IL-2 receptor induction. EMBO J 8: 757–764, 1989.[Web of Science][Medline]
114. Takagi Y, Mitsui A, Nishiyama A, Nozaki K, Sono H, Gon Y, Hashimoto N, Yodoi J. Overexpression of thioredoxin in transgenic mice attenuates focal ischemic brain damage. Proc Natl Acad Sci USA 96: 4131–4136, 1999.[Abstract/Free Full Text]
115. Takano H, Hasegawa H, Nagai T, Komuro I. Implication of cardiac remodeling in heart failure: mechanisms and therapeutic strategies. Intern Med 42: 465–469, 2003.[Web of Science][Medline]
116. Takano H, Zou Y, Hasegawa H, Akazawa H, Nagai T, Komuro I. Oxidative stress-induced signal transduction pathways in cardiac myocytes: involvement of ROS in heart diseases. Antioxid Redox Signal 5: 789–794, 2003.[CrossRef][Web of Science][Medline]
117. Tamura T, Stadtman TC. A new selenoprotein from human lung adenocarcinoma cells: purification, properties, and thioredoxin reductase activity. Proc Natl Acad Sci USA 93: 1006–1011, 1996.[Abstract/Free Full Text]
118. Tanito M, Masutani H, Nakamura H, Oka S, Ohira A, Yodoi J. Attenuation of retinal photooxidative damage in thioredoxin transgenic mice. Neurosci Lett 326: 142–146, 2002.[CrossRef][Web of Science][Medline]
119. Teshigawara K, Maeda M, Nishino K, Nikaido T, Uchiyama T, Tsudo M, Wano Y, Yodoi J. Adult T leukemia cells produce a lymphokine that augments interleukin 2 receptor expression. J Mol Cell Immunol 2: 17–26, 1985.[Web of Science][Medline]
120. Thompson RJ, Farragher SM, Cutz E, Nurse CA. Developmental regulation of O₂ sensing in neonatal adrenal chromaffin cells from wild-type and NADPH-oxidase-deficient mice. Pflügers Arch 444: 539–548, 2002.[CrossRef][Web of Science][Medline]
121. Thompson RJ, Jackson A, Nurse CA. Developmental loss of hypoxic chemosensitivity in rat adrenomedullary chromaffin cells. J Physiol 498: 503–510, 1997.[Abstract/Free Full Text]
122. Thornalley PJ, Dodd NJ. Free radical production from normal and adriamycin-treated rat cardiac sarcosomes. Biochem Pharmacol 34: 669–674, 1985.[CrossRef][Web of Science][Medline]
123. Tonissen K, Wells J, Cock I, Perkins A, Orozco C, Clarke F. Site-directed mutagenesis of human thioredoxin. Identification of cysteine 74 as critical to its function in the "early pregnancy factor" system. J Biol Chem 268: 22485–22489, 1993.[Abstract/Free Full Text]
124. Toutant C, Lippmann S. Fetal alcohol syndrome. Am Fam Physician 22: 113–117, 1980.[Web of Science][Medline]
125. Tristani-Firouzi M, Reeve HL, Tolarova S, Weir EK, Archer SL. Oxygen-induced constriction of rabbit ductus arteriosus occurs via inhibition of a 4-aminopyridine-, voltage-sensitive potassium channel. J Clin Invest 98: 1959–1965, 1996.[Web of Science][Medline]
126. Trocino RA, Akazawa S, Ishibashi M, Matsumoto K, Matsuo H, Yamamoto H, Goto S, Urata Y, Kondo T, Nagataki S. Significance of glutathione depletion and oxidative stress in early embryogenesis in glucose-induced rat embryo culture. Diabetes 44: 992–998, 1995.[Abstract]
127. Tsujita K, Shimomura H, Kaikita K, Kawano H, Hokamaki J, Nagayoshi Y, Yamashita T, Fukuda M, Nakamura Y, Sakamoto T, Yoshimura M, Ogawa H. Long-term efficacy of edaravone in patients with acute myocardial infarction. Circ J 70: 832–837, 2006.[CrossRef][Web of Science][Medline]
128. Turoczi T, Chang VW, Engelman RM, Maulik N, Ho YS, Das DK. Thioredoxin redox signaling in the ischemic heart: an insight with transgenic mice overexpressing Trx1. J Mol Cell Cardiol 35: 695–704, 2003.[CrossRef][Web of Science][Medline]
129. Ueno M, Masutani H, Arai RJ, Yamauchi A, Hirota K, Sakai T, Inamoto T, Yamaoka Y, Yodoi J, Nikaido T. Thioredoxin-dependent redox regulation of p53-mediated p21 activation. J Biol Chem 274: 35809–35815, 1999.[Abstract/Free Full Text]
130. Walsh RA. Effects of maternal smoking on adverse pregnancy outcomes: examination of the criteria of causation. Hum Biol 66: 1059–1092, 1994.[Web of Science][Medline]
131. Wang J, Kobayashi M, Sakurada K, Imamura M, Moriuchi T, Hosokawa M. Possible roles of an adult T-cell leukemia (ATL)-derived factor/thioredoxin in the drug resistance of ATL to adriamycin. Blood 89: 2480–2487, 1997.[Abstract/Free Full Text]
132. Wang Y, De Keulenaer GW, Lee RT. Vitamin D₃-up-regulated protein-1 is a stress-responsive gene that regulates cardiomyocyte viability through interaction with thioredoxin. J Biol Chem 277: 26496–26500, 2002.[Abstract/Free Full Text]
133. Webster KA, Graham RM, Thompson JW, Spiga MG, Frazier DP, Wilson A, Bishopric NH. Redox stress and the contributions of BH3-only proteins to infarction. Antioxid Redox Signal 8: 1667–1676, 2006.[CrossRef][Web of Science][Medline]
134. Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL. Acute oxygen-sensing mechanisms. N Engl J Med 353: 2042–2055, 2005.[Free Full Text]
135. Winn LM, Wells PG. Maternal administration of superoxide dismutase and catalase in phenytoin teratogenicity. Free Radic Biol Med 26: 266–274, 1999.[CrossRef][Web of Science][Medline]
136. Wold LE, Ceylan-Isik AF, Ren J. Oxidative stress and stress signaling: menace of diabetic cardiomyopathy. Acta Pharmacol Sin 26: 908–917, 2005.[CrossRef][Web of Science][Medline]
137. Wolin MS. Interactions of oxidants with vascular signaling systems. Arterioscler Thromb Vasc Biol 20: 1430–1442, 2000.[Abstract/Free Full Text]
138. Xu Z, Patel KP, Lou MF, Rozanski GJ. Up-regulation of K⁺ channels in diabetic rat ventricular myocytes by insulin and glutathione. Cardiovasc Res 53: 80–88, 2002.[Abstract/Free Full Text]
139. Yamada Y, Nakamura H, Adachi T, Sannohe S, Oyamada H, Kayaba H, Yodoi J, Chihara J. Elevated serum levels of thioredoxin in patients with acute exacerbation of asthma. Immunol Lett 86: 199–205, 2003.[CrossRef][Web of Science][Medline]
140. Yamamoto M, Yang G, Hong C, Liu J, Holle E, Yu X, Wagner T, Vatner SF, Sadoshima J. Inhibition of endogenous thioredoxin in the heart increases oxidative stress and cardiac hypertrophy. J Clin Invest 112: 1395–1406, 2003.[CrossRef][Web of Science][Medline]
141. Yoon BI, Hirabayashi Y, Kaneko T, Kodama Y, Kanno J, Yodoi J, Kim DY, Inoue T. Transgene expression of thioredoxin (TRX/ADF) protects against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced hematotoxicity. Arch Environ Contam Toxicol 41: 232–236, 2001.[CrossRef][Web of Science][Medline]
142. Yuan Z, Kishimoto C, Shioji K, Nakamura H, Yodoi J, Sasayama S. Temocapril treatment ameliorates autoimmune myocarditis associated with enhanced cardiomyocyte thioredoxin expression. Cardiovasc Res 55: 320–328, 2002.[Abstract/Free Full Text]
143. Zhao Z, Reece EA. Nicotine-induced embryonic malformations mediated by apoptosis from increasing intracellular calcium and oxidative stress. Birth Defects Res B Dev Reprod Toxicol 74: 383–391, 2005.[CrossRef][Web of Science][Medline]

This article has been cited by other articles:

				K. Ando, S. Hirao, Y. Kabe, Y. Ogura, I. Sato, Y. Yamaguchi, T. Wada, and H. Handa A new APE1/Ref-1-dependent pathway leading to reduction of NF-{kappa}B and AP-1, and activation of their DNA-binding activity Nucleic Acids Res., August 1, 2008; 36(13): 4327 - 4336. [Abstract] [Full Text] [PDF]

				D. K. Arrell, N. J. Niederlander, R. S. Faustino, A. Behfar, and A. Terzic Cardioinductive Network Guiding Stem Cell Differentiation Revealed by Proteomic Cartography of Tumor Necrosis Factor {alpha}-Primed Endodermal Secretome Stem Cells, February 1, 2008; 26(2): 387 - 400. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 292/5/H2040    most recent 01316.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Kobayashi-Miura, M. Articles by Yodoi, J. Search for Related Content PubMed PubMed Citation Articles by Kobayashi-Miura, M. Articles by Yodoi, J.