Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obstructive sleep apnea is associated with increased risk for cardiovascular diseases. As obstructive sleep apnea is characterized by episodic cycles of hypoxia and normoxia during sleep, we investigated effects of intermittent hypoxia (IH) on ischemia-reperfusion-induced myocardial injury. C57BL/6 mice were subjected to IH (2 min 6% O(2) and 2 min 21% O(2)) for 8 h/day for 1, 2, or 4 wk; isolated hearts were then subjected to ischemia-reperfusion. IH for 1 or 2 wk significantly enhanced ischemia-reperfusion-induced myocardial injury. However, enhanced cardiac damage was not seen in mice treated with 4 wk of IH, suggesting that the heart has adapted to chronic IH. Ischemia-reperfusion-induced lipid peroxidation and protein carbonylation were enhanced with 2 wk of IH, while, with 4 wk, oxidative stress was normalized to levels in animals without IH. H(2)O(2) scavenging activity in adapted hearts was higher after ischemia-reperfusion, suggesting the increased antioxidant capacity. This might be due to the involvement of thioredoxin, as the expression level of this protein was increased, while levels of other antioxidant enzymes were unchanged. In the heart from mice treated with 2 wk of IH, ischemia-reperfusion was found to decrease thioredoxin. Ischemia-reperfusion injury can also be enhanced when thioredoxin reductase was inhibited in control hearts. These results demonstrate that IH changes the susceptibility of the heart to oxidative stress in part via alteration of thioredoxin.
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PMID:Effects of intermittent hypoxia on oxidative stress-induced myocardial damage in mice. 1727 4

A recent study showed that cardiac adaptation could potentiate translocation of thioredoxin-1 (Trx-1) into the nucleus, which then interacted with Ref-1, resulting in a survival signal. Here, we present evidence that such adaptation also causes nuclear translocation of Ref-1, which is almost completely inhibited when the hearts were pretreated with antisense Ref-1 that also abolished the cardioprotective adaptive response. Significant amounts of NFkappaB and Nrf2 were found to be associated with Ref-1 when the nuclear extract obtained from the left ventricle was immunoprecipitated with Ref-1. Such Ref-1-NFkappaB and Ref-1-Nrf2 interactions were significantly inhibited with antisense Ref-1. However, immunoprecipitation of nuclear extract with NFkappaB showed that the association of Trx-1 with NFkappaB is increased in the adapted heart, which was again significantly blocked by antisense Ref-1. Nrf2 was also associated with NFkappaB; however, such association appeared to be independent of Ref-1. In contrast, myocardial adaptation to ischemia inhibited the ischemia reperfusion-induced loss of Nrf2 from the nucleus, which was inhibited by antisense Ref-1. The nuclear translocation and activation of Ref-1 appeared to generate a survival signal as evidenced by the increased phosphorylation of Akt that was inhibited with antisense Ref-1. Finally, confocal microscopy confirmed the results of immunoblotting, clearly showing the nuclear translocation of Ref-1 and nuclear 3D colocalization of Ref-1 with NFkappaB in the adapted heart and its inhibition with antisense Ref-1. Our results show that PC potentiates a survival signal through the phosphorylation of Akt by causing nuclear translocation and activation of Ref-1, where significant interaction among NFkappaB and Ref-1, Trx-1, and Nrf2 appears to regulate Ref-1-induced survival signal.
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PMID:Redox activation of Ref-1 potentiates cell survival following myocardial ischemia reperfusion injury. 1760 55

This study examined if glutaredoxin-1 (Glrx1), a redox-regulator of thioredoxin superfamily, plays any role in the redox signaling of ischemic myocardium. The hearts were subjected to 30 min of coronary occlusion followed by 24 h of reperfusion. Another group of hearts was rendered tolerant to ischemia (preconditioned, PC) by four cyclic episodes of 5 min ischemia each followed by another 10 min of reperfusion, which was then subjected to 30 min ischemia and 24 h of coronary occlusion. While ischemia/reperfusion had no effect on Glrx1 expression, adaptation to ischemia resulted in the up-regulation of Glrx1 expression, which was inhibited by cadmium, a known inhibitor of Glrx1. CdCl(2) also abolished cardioprotection afforded by PC as evidenced by its ability to partially increase myocardial infarct size without affecting cardiomyocyte apoptosis. The amount of ROS was significantly decreased in the PC heart, which was abolished by CdCl(2). The cardioprotective role of Glrx1was further confirmed with Glrx1 transgenic and knockout mice. The mouse hearts overexpressing Glrx1 exhibited significantly improved post-ischemic ventricular recovery and reduced myocardial infarct size while hearts deficient in Glrx1 exhibited depressed functional recovery and increased infarct size as compared to the wild-type hearts. Furthermore, Glrx1-overexpressing hearts exhibited reduced and Glrx1-deficient hearts exhibited increased ROS production during ischemia and reperfusion. Adapted hearts showed increased Akt phosphorylation that was inhibited by CdCl(2). The amount of Bcl-2 protein expression was not affected by the inhibition of Glrx1. Taken together, the results of this study implicate a role of Glrx1 in cardioprotection and redox signaling of the ischemic myocardium.
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PMID:Role of glutaredoxin-1 in cardioprotection: an insight with Glrx1 transgenic and knockout animals. 2323 Jun 6

In this study, we determined the changes in the intracellular redox environment of the heart during ischemia and reperfusion and the effects of resveratrol on such changes. Because redox regulation by thioredoxin (Trx) plays a crucial role in signal transduction and cytoprotection against ROS, the effects of resveratrol on the changes in the amounts of thioredoxin were monitored in an attempt to determine the role of intracellular thioredoxin in resveratrol-mediated changes in intracellular redox environment and its role in resveratrol-mediated cardioprotection. Rats were randomly divided into four groups: group I, control (rats were gavaged with vehicle only); group II, rats were gavaged with 2.5 mg/kg body wt resveratrol per day for 10 days; group III, rats were given resveratrol for 10 days, but on the 7th day, they were treated with shRNA against Trx-1; group IV, rats were given resveratrol for 10 days, but were injected (iv) with cisplatin (1 mg/kg body wt) on days 1, 3, 5, 7, and 9. In concert, two groups of mice (Dn-Trx-1) and a corresponding wild-type group were also gavaged with 2.5 mg/kg body wt resveratrol for 10 days. After 10 days, isolated rat and mouse hearts perfused via working mode were made globally ischemic for 30 min followed by 2 h of reperfusion. Ischemia/reperfusion developed an infarct size of about 40% and resulted in about 25% apoptotic cardiomyocytes, which were reduced by resveratrol. Cisplatin, but not shRNA-Trx-1, abolished the cardioprotective abilities of resveratrol. In the experiments with mouse hearts, similar to rat hearts, resveratrol significantly reduced the ischemia/reperfusion-mediated increase in infarct size and apoptosis in both groups. MDA formation, a presumptive marker for lipid peroxidation, was increased in the I/R group and reduced in the resveratrol group, and resveratrol-mediated reduction in MDA formation was abolished with cisplatin, but not with shRNA-Trx-1. I/R-induced reduction in GSH/GSSH ratio was prevented by resveratrol, and resveratrol-mediated preservation of GSH/GSSG ratio was reduced by cisplatin, but not by sh-RNA-Trx-1. RT-PCR revealed an increase in both Trx-1 and Trx-2 transcripts; but only Trx-2 protein, not Trx-1 protein, was enhanced with resveratrol by Western blot analysis. Electron paramagnetic resonance spectroscopic study revealed that resveratrol treatment significantly increased the decay rates of nitroxide radicals compared to control hearts, suggesting that resveratrol can switch into the reduction state more compared to control heart. Finally, resveratrol generated a survival signal by phosphorylation of Akt and increase in induction of Bcl-2 expression, which was inhibited by cisplatin, but not by shRNA-Trx-1. Taken together, the results of this study indicate that resveratrol provides cardioprotection by maintaining intracellular redox environments, and Trx-2 is likely to play a role in switching I/R-induced death signal into survival signal.
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PMID:Redox regulation of resveratrol-mediated switching of death signal into survival signal. 2301 55

Epidemiological evidence indicates several health benefits of the consumption of broccoli, especially related to chemoprevention. Because broccoli contains high amounts of selenium and glucosinolates (particularly glucoraphanin and isothiocyanate sulforaphane), which can produce redox-regulated cardioprotective protein thioredoxin (Trx), it was reasoned that consumption of broccoli could be beneficial to the heart. To test this hypothesis, a group of rats were fed broccoli (slurry made with water) through gavaging; control animals were gavaged water only. After 30 days, the rats were sacrificed; isolated hearts perfused via working mode were made ischemic for 30 min followed by 2 h of reperfusion. The results demonstrated significant cardioprotection with broccoli as evidenced by improved postischemic ventricular function, reduced myocardial infarct size, and decreased cardiomyocyte apoptosis accompanied by reduced cytochrome c release and increased pro-caspase 3 activities. Ischemia/reperfusion reduced both RNA transcripts and protein levels of the thioredoxin superfamily including Trx1, Trx2, glutaredoxin Grx1, Grx2, and peroxiredoxin (Prdx), which were either restored or enhanced with broccoli. Broccoli enhanced the expression of Nrf2, a cytosolic suppressor of Keap1, suggesting a role of antioxidant response element (ARE) in the induction of Trx. Additionally, broccoli induced the expression of another cardioprotective protein, heme oxygenase (HO)-1, which could be transactivated during the activation of Trx. Examination of the survival signal revealed that broccoli caused the phosphorylation of Akt and the induction of Bcl2 in concert with the activation of redox-sensitive transcription factor NF kappa B and Src kinase, indicating a role of Akt, Bcl2, and cSrc in the generation of survival signal. Taken together, the results of the present study indicate that the consumption of broccoli triggers cardioprotection by generating a survival signal through the activation of several survival proteins and by redox cycling of thioredoxins.
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PMID:Broccoli: a unique vegetable that protects mammalian hearts through the redox cycling of the thioredoxin superfamily. 2241 31

The thioredoxin (TRX) system consists of TRX, TRX reductase, and NAD(P)H, and is able to reduce reactive oxygen species (ROS) through interactions with the redox-active center of TRX, which in turn can be reduced by TRX reductase in the presence of NAD(P)H. Among the TRX superfamily is peroxiredoxin (PRX), a family of non-heme peroxidases that catalyzes the reduction of hydroperoxides into water and alcohol. The TRX system is active in the vessel wall and functions either as an important endogenous antioxidant or interacts directly with signaling molecules to influence cell growth, apoptosis, and inflammation. Recent evidence implicates TRX in cardiovascular disease associated with oxidative stress, such as cardiac failure, arrhythmia, ischemia reperfusion injury, and hypertension. Thioredoxin activity is influenced by many mechanisms, including transcription, protein-protein interaction, and post-translational modification. Regulation of TRX in hypertensive models seems to be related to oxidative stress and is tissue- and cell-specific. Depending on the models of hypertension, TRX system could be upregulated or downregulated. The present review focuses on the role of TRX in vascular biology, describing its redox activities and biological properties in the media and endothelium of the vessel wall. In addition, the pathopysiological role of TRX in hypertension and other cardiovascular diseases is addressed.
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PMID:Thioredoxin in vascular biology: role in hypertension. 1831 95

Angiogenesis is essential for tumor growth, metastasis, arteriosclerosis as well as embryonic development and wound healing. Its process is dependent on cell proliferation, migration and capillary tube formation in endothelia cells (ECs). High levels of reactive oxygen species (ROS) such as superoxide and H2O2 are observed in various cancer cells. Accumulating evidence suggests that ROS function as signaling molecules to mediate various growth-related responses including angiogenesis. ROS-dependent angiogenesis can be regulated by endogenous antioxidant enzymes such as SOD and thioredoxin. Vascular endothelial growth factor (VEGF), one of the major angiogenesis factor, is induced in growing tumors and stimulates EC proliferation and migration primarily through the VEGF receptor type2 (VEGFR2, Flk1/KDR). Major source of ROS in ECs is a NADPH oxidase which consists of Nox1, Nox2, Nox4, Nox5, p22phox, p47phox and the small G-protein Rac1. NADPH oxidase is activated by various growth factors including VEGF and angiopoietin-1 as well as hypoxia and ischemia, and ROS derived from this oxidase are involved in VEGFR2 autophosphorylation, and diverse redox signaling pathways leading to induction of transcription factors and genes involved in angiogenesis. Dietary antioxidants appear to be effective for treatment of tumor angiogenesis. The aim of this review is to provide an overview of the recent progress on role of ROS derived from NADPH oxidase and redox signaling events involved in angiogenesis. Understanding these mechanisms may provide insight into the NADPH oxidase and redox signaling components as potential therapeutic targets for tumor angiogenesis.
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PMID:Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. 1840 51

Hydrogen sulfide (H(2)S) is an endogenously produced gaseous signaling molecule with diverse physiological activity. The potential protective effects of H(2)S have not been evaluated in the liver. The purpose of the current study was to investigate if H(2)S could afford hepatoprotection in a murine model of hepatic ischemia-reperfusion (I/R) injury. Hepatic injury was achieved by subjecting mice to 60 min of ischemia followed by 5 h of reperfusion. H(2)S donor (IK1001) or vehicle were administered 5 min before reperfusion. H(2)S attenuated the elevation in serum alanine aminotransferase (ALT) by 68.6% and aspartate aminotransferase (AST) by 70.8% compared with vehicle group. H(2)S-mediated cytoprotection was associated with an improved balance between reduced glutathione (GSH) vs. oxidized glutathione (GSSG), an attenuated formation of lipid hydroperoxides, and an increased expression of thioredoxin-1 (Trx-1). Furthermore, H(2)S inhibited the progression of apoptosis after I/R injury by increasing the protein expression of heat shock protein (HSP-90) and Bcl-2. These results indicate that H(2)S protects the murine liver against I/R injury through an upregulation of intracellular antioxidant and antiapoptotic signaling pathways.
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PMID:Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and antiapoptotic signaling. 1856 6

Recent studies have demonstrated the cardioprotective abilities of resveratrol, a polyphenolic antioxidant present in red wine. Resveratrol can also kill cancer cells at relatively higher doses by exerting a death signal. We reasoned that resveratrol might possess the ability to protect the cells at lower doses as observed during pharmacological preconditioning of the heart, while at higher doses cause cell death as found for cancer cells. To test this hypothesis, rats were randomly fed for 14 days by gavaging any of the four doses of resveratrol - 2.5, 5.0, 25 or 50 mg/kg - while vehicle-fed animals served as placebo control. After 14 days, isolated working hearts were prepared from both experimental and control animals, and the hearts were subjected to 30-min global ischemia followed by 2 h of reperfusion. The rats fed either 2.5 or 5 mg/kg dose of resveratrol for 14 days provided cardioprotection as evidenced by improved post-ischemic ventricular recovery and reduction of myocardial infarct size and cardiomyocyte apoptosis compared to control. In contrast, the hearts fed either 25 or 50 mg/kg dose of resveratrol depressed cardiac function and increased myocardial infarct size and number of apoptotic cells. The results for Western blots and RT-PCR demonstrated an increase of protein and RNA transcripts of redox proteins including thioredoxin (Trx)-1, Trx-2, glutaredoxin (Grx)-1, Grx-2, redox factor Ref-1 as well as redox-sensitive transcription factor NFkappaB, and survival factors such as phosphorylated-Akt (p-Akt), and Bcl-2 in the animals fed lower doses (2.5 and 5 mg/kg) of resveratrol, while the reverse was true for the animals fed higher doses (25 and 50 mg/kg) of resveratrol. The results thus indicate that at lower doses (2.5 or 5 mg/kg), resveratrol exerts survival signal by up-regulating anti-apoptotic and redox proteins Akt and Bcl-2, while at higher doses (>25 mg/kg), it potentiates a death signal by down-regulating redox proteins and up-regulating pro-apoptotic proteins.
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PMID:Resveratrol, a unique phytoalexin present in red wine, delivers either survival signal or death signal to the ischemic myocardium depending on dose. 2289 70

The purpose of this study was to explore the therapeutic time window and mechanism of tetramethylpyrazine on transient focal cerebral ischemia/reperfusion injury. Middle cerebral artery occlusion was conducted in male Sprague-Dawley rats and 20mg/kg tetramethylpyrazine was injected intraperitoneally at different time points. Neurological deficit scores and brain infarction volumes were measured 72 h after reperfusion started. The expression of thioredoxin and thioredoxin reductase were examined at 6h and at 24h after reperfusion. Our results included the findings of a significant reduction in neurological deficit scores and infarction volume in the treatment group as compared to the control group. Ischemia/reperfusion injury resulted in a decrease in the expression of thioredoxin, while tetramethylpyrazine administration greatly elevated the expression of thioredoxin-1/thioredoxin-2 mRNA and thioredoxin reductase-1/thioredoxin reductase-2 mRNA. These findings suggest that administration of tetramethylpyrazine, within a 4h time period post-transient focal stroke, may reduce cerebral ischemic reperfusion damage. Moreover, the neuroprotective effect of tetramethylpyrazine may be mediated, in part, by an increase in genetic transcription of thioredoxin.
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PMID:Therapeutic time window and mechanism of tetramethylpyrazine on transient focal cerebral ischemia/reperfusion injury in rats. 1879 5


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