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

According to their demonstrated activities, the thiol-disulfide oxidoreductase (TDOR) enzyme systems [thioltransferase (glutaredoxin) and GSSG reductase; and thioredoxin and thioredoxin reductase] are expected to provide the primary cellular mechanism for protection and repair of sulfhydryl proteins under oxidative stress. Since all four enzymes have active site dithiol moieties, they may be vulnerable to oxidative damage themselves. Therefore, an hydroxyl radical generating system (chelated ferrous iron in combination with hydrogen peroxide) was used to document the relative sensitivity of each of the enzymes to oxidative stress in vitro. At particular concentrations of enzymes and oxidant system, all of the enzymes were deactivated nearly completely, but different patterns of susceptibility were observed. At the approximate physiological concentration of each enzyme thioredoxin and thiol-transferase were largely deactivated with 1 mM Fe2+-ADP, 1 mM H2O2; whereas thioredoxin reductase and GSSG reductase were much less sensitive: 10 microM thioredoxin (88% deactivated), 1 microM thioltransferase (72%), 2 microM thioredoxin reductase (5%), and 0.1 microM GSSG reductase (17%). As the concentration of the oxidant system was decreased stepwise from 1 mM to 1 microM to mimic conditions that may be associated with oxidative tissue injury in situ, deactivation of thioredoxin was decreased proportionately, whereas thioltransferase remained much more susceptible. As expected GSH and other radical scavengers protected thioltransferase from deactivation by Fe(ADP)-H2O2. To test the susceptibility of the TDOR enzymes to oxidative stress in a physiological-like setting, isolated perfused rabbit hearts were subjected to 30 min ischemia and 30 min reperfusion. The GSH/GSSG ratio and total dethiolase activity (thioltransferase and thioredoxin systems) remained unchanged relative to control hearts, indicating that overall redox status and sulfhydryl repair activity are maintained during moderate oxidative stress in situ.
 ...
PMID:Sensitivity of protein sulfhydryl repair enzymes to oxidative stress. 921 73

We investigated the distribution of glutaredoxin (GRX, thioltransferase) in the rat brain using the in situ hybridization and immunohistochemical methods. GRX mRNA and GRX were expressed widely in the rat brain. The endothelial cell, tanycyte and ependymal cell expressed GRX mRNA and GRX protein. Neurons in various regions also showed GRX mRNA and GRX. Among them, pyramidal neurons in hippocampal CA3 region expressed a higher level of GRX mRNA. In addition, GRX mRNA signals were reduced after middle cerebral artery occlusion. Immunohistochemical analysis for GRX also revealed that GRX was reduced after ischemia. Northern blot analysis also showed that GRX mRNA from ischemic hemispheres decreased after ischemia. This reduction was parallel with the neuronal damage. This observation indicated that the maintenance of GRX and the redox regulating system was important for neuronal survival against oxidative stress.
 ...
PMID:Localization of glutaredoxin (thioltransferase) in the rat brain and possible functional implications during focal ischemia. 1032 97

Reactive oxygen species (ROS) and the cellular thiol redox state are crucial mediators of multiple cell processes like growth, differentiation, and apoptosis. Excessive ROS production or oxidative stress is associated with several diseases, including cardiovascular disorders like ischemia-reperfusion. To prevent ROS-induced disorders, the heart is equipped with effective antioxidant systems. Key players in defense against oxidative stress are members of the thioredoxin-fold family of proteins. Of these, thioredoxins and glutaredoxins maintain a reduced intracellular redox state in mammalian cells by the reduction of protein thiols. The reversible oxidation of Cys-Gly-Pro-Cys or Cys-Pro(Ser)-Tyr-Cys active site cysteine residues is used in reversible electron transport. Thioredoxins and glutaredoxins belong to corresponding systems consisting of NADPH, thioredoxin reductase, and thioredoxin or NADPH, glutathione reductase, glutathione, and glutaredoxin, respectively. Thioredoxin as well as glutaredoxin activities appear to be very important for the progression and severity of several cardiovascular disorders. These proteins function not only as antioxidants, they inhibit or activate apoptotic signaling molecules like apoptosis signal-regulating kinase 1 and Ras or transcription factors like NF-kappaB. Thioredoxin activity is regulated by the endogenous inhibitor thioredoxin-binding protein 2 (TBP-2), indicating an important role of the balance between thioredoxin and TBP-2 levels in cardiovascular diseases. In this review, we will summarize cardioprotective effects of endogenous thioredoxin and glutaredoxin systems as well as the high potential in clinical applications of exogenously applied thioredoxin or glutaredoxin or the induction of endogenous thioredoxin and glutaredoxin systems.
 ...
PMID:Thiol-based mechanisms of the thioredoxin and glutaredoxin systems: implications for diseases in the cardiovascular system. 1717 68

To understand the physiological function of glutaredoxin, a thiotransferase catalyzing the reduction of mixed disulfides of protein and glutathione, we generated a line of knockout mice deficient in the cytosolic glutaredoxin 1 (Grx1). To our surprise, mice deficient in Grx1 were not more susceptible to acute oxidative insults in models of heart and lung injury induced by ischemia/reperfusion and hyperoxia, respectively, suggesting that either changes in S-glutathionylation status of cytosolic proteins are not the major cause of such tissue injury or developmental adaptation in the Glrx1-knockout animals alters the response to oxidative insult. In contrast, mouse embryonic fibroblasts (MEFs) isolated from Grx1-deficient mice displayed an increased vulnerability to diquat and paraquat, but they were not more susceptible to cell death induced by hydrogen peroxide (H(2)O(2)) and diamide. A deficiency in Grx1 also sensitized MEFs to protein S-glutathionylation in response to H(2)O(2) treatment and retarded deglutathionylation of the S-glutathionylated proteins, especially for a single prominent protein band. Additional experiments showed that MEFs lacking Grx1 were more tolerant to apoptosis induced by tumor necrosis factor alphaplus actinomycin D. These findings suggest that various oxidants may damage the cells via distinct mechanisms in which the action of Grx1 may or may not be protective and Grx1 may exert its function on specific target proteins.
 ...
PMID:Targeted disruption of the glutaredoxin 1 gene does not sensitize adult mice to tissue injury induced by ischemia/reperfusion and hyperoxia. 1789 43

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.
 ...
PMID:Role of glutaredoxin-1 in cardioprotection: an insight with Glrx1 transgenic and knockout animals. 2323 Jun 6

Mitochondrial glutaredoxin-2 (Glrx2) has been recognized as an important redox regulator in mammalian organs including heart. To date no investigations have addressed the potential role of Glrx2 in cardiac disorders. The present study examined if myocardial overexpression of Glrx2 in the heart could rescue the cardiac cells from apoptosis and necrosis induced by ischemia and reperfusion. The human Glrx2 transgene was created by placing a full-length cDNA fragment encoding human mitochondrial Glrx2 downstream to the 5' flanking sequence and promoter of the mouse alpha-myosin heavy chain gene. The isolated hearts from Glrx2 transgenic mice and non-transgenic (wild type) littermates [on c57BL/6xC3H hybrid background] were subjected to 30 min of global ischemia followed by 2 h of reperfusion via working mode. The hearts from Glrx2 transgenic mice displayed significantly improved contractile performance and reduced myocardial infarct size and cardiomyocyte apoptosis. There was a reduction in cytochrome c release and activation of caspase 3 and caspase 9. Glrx2 overexpression also reduced the ischemia/reperfusion-mediated loss of mitochondrial cardiolipin, decreased the activities of reactive oxygen species (ROS) and preserved GSH/GSSG ratio. Glrx2 mediated survival signal appeared to be stemmed from PI-3-kinase-Akt survival signaling pathway and involved the activation of redox sensitive transcription factor NFkappaB and antiapoptotic protein Bcl-2. The results indicated a crucial role of mitochondrial Glrx2 in cardioprotection.
 ...
PMID:Overexpression of glutaredoxin-2 reduces myocardial cell death by preventing both apoptosis and necrosis. 2323 Jun 5

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.
 ...
PMID:Broccoli: a unique vegetable that protects mammalian hearts through the redox cycling of the thioredoxin superfamily. 2241 31

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.
 ...
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

Cytosolic NADP+-dependent isocitrate dehydrogenase (IDPc) is susceptible to inactivation by numerous thiol-modifying reagents. This study now reports that Cys269 of IDPc is a target for S-glutathionylation and that this modification is reversed by dithiothreitol as well as enzymatically by cytosolic glutaredoxin in the presence of GSH. Glutathionylated IDPc was significantly less susceptible than native protein to peptide fragmentation by reactive oxygen species and proteolytic digestion. Glutathionylation may play a protective role in the degradation of protein through the structural alterations of IDPc. HEK293 cells treated with diamide displayed decreased IDPc activity and accumulated glutathionylated enzyme. Using immunoprecipitation with an anti-IDPc IgG and immunoblotting with an anti-GSH IgG, we purified and positively identified glutathionylated IDPc from the kidneys of mice subjected to ischemia/reperfusion injury and from the livers of ethanol-administered rats. These results suggest that IDPc activity is modulated through enzymatic glutathionylation and deglutathionylation during oxidative stress.
 ...
PMID:Glutathionylation regulates cytosolic NADP+-dependent isocitrate dehydrogenase activity. 1929 92

CLP-1, the mouse homologue of human Hexim1 protein, exerts inhibitory control on transcriptional elongation factor-b of RNA transcript elongation. Previously, we have demonstrated that downregulation of cardiac lineage protein-1 (CLP-1) in CLP-1(+/-) heterozygous mice affords cardioprotection against ischemia-reperfusion injury. Our current study results show that the improvement in cardiac function in CLP-1(+/-) mice after ischemia-reperfusion injury is achieved through the potentiation of redox signaling and their molecular targets including redox effector factor-1, nuclear factor erythroid 2-related factor, and NADPH oxidase 4 and the active usage of thioredoxin-1, thioredoxin-2, glutaredoxin-1 and glutaredoxin-2. Our results suggest that drugs designed to down regulate CLP-1 could confer cardioprotection through the potentiation of redox cycling.
 ...
PMID:Downregulation of cardiac lineage protein-1 confers cardioprotection through the upregulation of redox effectors. 1993 34


1 2 3 Next >>