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Oxygen Sensing: Life and Death of a Cell
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
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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).
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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.
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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.
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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.
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