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J Thorac Cardiovasc Surg 2003;125:650-660
© 2003 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology |
B-dependent mechanism in the rat heart
From the Crafoord Laboratory of Experimental Surgerya and the Department of Thoracic Surgery,b Karolinska Hospital, Stockholm, Sweden, and the Institute of Biochemistry and Clinic of Anesthesiology and Intensive Care,c University of Tartu, Tartu, Estonia.
Grants were received from the Swedish Medical Research Council (11235 and 12665), The Swedish Heart-Lung Foundation, the Foundations Fredrik o Ingrid Thuring, Tore Nilsson, Åke Wiberg, The Laerdahl Foundation for Acute Medicine, Sigurd and Elsa Goljes Memory, AGA Gas, Gösta Franckel's Foundation, and the Karolinska Institutet. P.T. has been recipient of a grant from Karolinska Institutet.
Received for publication Nov 29, 2001. Revisions requested Jan 8, 2002; revisions received July 28, 2002. Accepted for publication Aug 6, 2002. Address for reprints: Guro Valen, MD, PhD, Crafoord Laboratory of Experimental Surgery, L6:00, Karolinska Hospital, S-171 76 Stockholm, Sweden (E-mail: Guro.Valen{at}cmm.ki.se).
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B. 
95% O2) environment for 60 minutes. Their hearts were isolated immediately afterward, buffer perfused in a Langendorff apparatus, and subjected to 25 minutes of global ischemia and 60 minutes of reperfusion. Cardiac pressures and coronary flow were measured, and infarct size was determined by means of triphenyl tetrazolium chloride staining. Activation of nuclear factor B was assessed by means of the electrophoretic mobility shift assay, whereas the inhibitor IB
was evaluated by means of immunoblotting. Pharmacologic inhibition of nuclear factor B was achieved with 2 different agents, SN50 and pyrrolidine dithiocarbamate. B. Pretreatment with SN50 (400 µg/kg administered intraperitoneally) or pyrrolidine dithiocarbamate (100 mg/kg administered intraperitoneally) before hyperoxia abolished the functional and infarct-limiting protection. Hyperoxia reduced nuclear factor B activation in the heart during sustained ischemia and reperfusion and increased the cytoplasmatic inhibitory factor IB. Administration of pyrrolidine dithiocarbamate or SN50 during ischemia and reperfusion to isolated hearts from normoxic control animals improved postischemic contractile function and coronary flow and reduced infarct size. B. Our results support evidence for a dual role of nuclear factor B in the heart. |
Introduction |
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1,2 However, hyperoxia might lead to excessive generation of reactive oxygen species and cause tissue injury. 3
Reactive oxygen species are involved in the regulation of a number of cellular processes. 4 Transcription factors, such as nuclear factor B (NFB) and activator protein 1 (AP-1), are, to a great extent, controlled by oxidative stress. 5 NFB and AP-1 are involved in the early activation of genes in response to various types of cell stress alone or in cooperation with each other. Under normal physiologic conditions, NFB is held in the cytoplasm in an inactive form by the inhibitory protein IB. During cellular stress, IB is phosphorylated and released from the NFB homodimer or heterodimer. 5 NFB translocates to the cell nucleus, binds to promoter-enhancer regions of the genes it regulates, and induces their transcription. NFB regulates a battery of genes associated with proinflammatory effects, such as leukocyte adhesion molecules, cytokines, and chemokines. 5,6 NFB also regulates genes that might be associated with tissue repair and protection, such as the genes encoding inducible nitric oxide synthase and inducible cyclooxygenase and the antioxidant manganese superoxide dismutase. 6,7
Recent studies have suggested that NFB plays an essential role in ischemic preconditioning, an endogenous phenomenon by which short periods of ischemia and reperfusion can protect the heart against a subsequent sustained ischemic insult. 8,9 Inhibition of NFB activation during adaptation to ischemia abolished the functional protection and infarct-limiting effect of ischemic preconditioning. 8,10 However, activation of NFB in ischemia-reperfusion injury without prior adaptation appears to be detrimental because inhibition of NFB activation reduced infarct size and improved heart function. 11,12 Thus the role of NFB in myocardial ischemia and reperfusion might be dual, with both a cardioprotective role in ischemic preconditioning and a detrimental role during sustained ischemia and reperfusion.
We have previously shown that breathing a hyperoxic gas (95% O2) induces systemic low-grade oxidative stress in rats, which is evident as increased systemic conjugated dienes, and improves heart function and reduces myocardial necrosis after ischemia-reperfusion injury. 13 The purpose of this study was to investigate whether this preconditioning-like response was dependent on NFB.
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Rat heart perfusion
Details of heart isolation and perfusion are provided elsewhere. 13 Briefly, male Sprague-Dawley rats (250-300 g) were anesthetized with midazolam (Dormicum; 1.5 mg/kg administered intramuscularly) and fentanyl-fluanisone (Hypnorm; 0.1 mg/kg fentanyl and 3 mg/kg fluanisone administered intramuscularly). Heparin (200 IU) was injected into the femoral vein, and thereafter, the hearts were excised and the aorta was cannulated. The hearts were retrogradely Langendorff perfused with gassed (5% CO2, 95% O2, pH 7.35-7.45) Krebs-Henseleit buffer at 37°C at a constant pressure of 70 mm Hg. Isovolumetric recordings of left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP) were obtained by using a balloon inserted into the left ventricle through the left atrium. LVEDP was set to 5 mm Hg at the end of the stabilization period. Coronary flow (CF) was measured by means of timed collections of the coronary effluent. Left ventricular developed pressure (LVDP) was calculated as follows:
LVDP = LVSP - LVEDP.
Heart rate (HR) was counted from the pressure curves. Global ischemia was achieved by clamping the inflow tubing.
The experimental protocol is shown in Figure 1. Before heart isolation and Langendorff perfusion, the rats were kept for 60 minutes in a cage, where a normoxic (atmospheric air) or hyperoxic (95% O2, monitoring with a gas analyzer) environment was established. The length of hyperoxia was selected on the basis of previous studies. 13 Immediately after exposure to hyperoxia or normoxia, the hearts were excised and buffer perfused by using the Langendorff technique with 25 minutes of stabilization, 25 minutes of global ischemia, and 60 minutes of reperfusion. Only hearts with an LVSP of 60 to 160 mm Hg, a CF of 8 to 16 mL/min, and an HR of 240 to 360 beats/min at the end of stabilization were included. The NFB inhibitors SN50 (400 µg/kg; Calbiochem-Novabiochem Corp) or pyrrolidine dithiocarbamate (PDTC; 100 mg/kg; Sigma Chemical Co) were injected intraperitoneally 20 minutes before 60 minutes of hyperoxia or normoxia, followed by Langendorff perfusion (groups 3-6 in Figure 1, respectively). Studies investigating the effects of SN50 or PDTC on hyperoxia-induced myocardial protection were performed at a different calendar time and are accompanied by separate normoxic control and hyperoxic groups. Selection of drug concentrations and routes of administration were based on pilot studies on functional effects (results not shown).
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B inhibition during reperfusion influences ischemia-reperfusion injury in isolated hearts. Hearts were harvested from normoxic control animals, isolated, and buffer perfused. Starting from 3 minutes before global ischemia and throughout reperfusion, SN50 (18 µmol/L final concentration) 8 or PDTC (1 mmol/L) 14 was added to the perfusion buffer. During the preischemic period, the drugs had no effect on baseline functional variables (LVEDP, LVDP, HR, and CF).
Determination of infarct size
At the end of reperfusion, the hearts were perfused with 1% triphenyl tetrazolium chloride (TTC; Sigma Chemical Co) at a total volume of 3.0 mL delivered at 70 mm Hg. TTC stains viable tissue red, whereas necrotic tissue remains unstained. The hearts were fixed in 4% formaldehyde for 24 hours and thereafter preserved in 10% sucrose in phosphate-buffered saline. The hearts were cut manually into 1-mm transverse slices. The sections were visualized with a computer imaging system (LEICA Qwin; Leica Imaging Systems), and infarct size was calculated by using Adobe Photoshop 5.0. The infarcted area was calculated as a percentage of total myocardial area. From each slice, an image was obtained from both sides, and all calculations from one heart were averaged into one value for statistics.
Tissue sampling for molecular biology
Additional hearts and lungs were sampled for tissue analysis. The hearts were freeze clamped at the end of 60 minutes of hyperoxia (n = 7) or normoxia (n = 7) for nuclear protein extraction and electrophoretic mobility shift assay (EMSA) to evaluate whether hyperoxia resulted in myocardial NFB activation. Hearts of 3 animals injected with SN50 before hyperoxia were analyzed to assess the effect of SN50 on myocardial NFB activation. These organs were freeze clamped after exposure to 0, 2, 5, 10, 20, or 60 minutes of hyperoxia (n = 3 of each tissue for each time point) to evaluate the time course of NFB activation in lungs and hearts. Finally, the hearts were sampled for immunoblotting serially during stabilization, ischemia, and reperfusion (n = 3 from each group at each time point) to investigate whether hyperoxia influenced NFB activation and content of the NFB inhibitor IB.
Preparation of nuclear protein extracts
Nuclear proteins were extracted from frozen heart samples, as previously described in detail. 15 Briefly, hearts were homogenized in a microdismembrator, and lysis buffer was added. After incubation on ice, nuclei were collected by means of centrifugation for 1 minute at 8000g. The pellet was washed with 20 mmol/L KCl buffer, centrifuged, and resuspended in 20 mmol/L KCl buffer, and 0.6 mol/L KCl was added and kept at +4°C for 30 minutes. After centrifugation for 15 minutes at 8000g, the supernatant containing nuclear proteins was obtained. The protein concentration was determined by using the bicinchonic acid reagent (Pierce, Rockford, Ill) with bovine serum albumin as a standard.
Electrophoretic mobility shift assay
Nuclear extracts (16 µg of protein per lane) were preincubated for 10 minutes in binding buffer (20 mmol/L Hepes [pH 7.9], 5% glycerol, 5 mmol/L MgCl2, 0.5 mmol/L ethylenediamine tetraacetic acid, and 1 mmol/L dithiothreitol), followed by 30 minutes' incubation at room temperature with 50,000 cpm of phosphorous 32-labeled probe containing the NFB binding site 5' AGT TGA GGG GAC TTT CCC AGG C or the AP-1 binding site 5' CGC TTG ATG AGT CAG CCC GGA A (both from Promega Biosciences, Inc). DNA-protein complexes were electrophoresed on a 4% polyacrylamide gel. For supershift analysis, a rabbit polyclonal anti-p50 antibody or a rabbit polyclonal anti-c-jun antibody (both Santa Cruz Biotechnology) were incubated with the binding buffer for 15 minutes before adding the radiolabeled probe. For competition analysis, unlabeled probe in 100-fold excess was added before radiolabeled probe. Quantification of band densities was performed with the software Tina 2.0. Only bands on the same gel were used for calculation and comparison.
Immunoblotting
Cytoplasmatic cardiac proteins were extracted by homogenizing frozen tissue at a ratio of 40 mg of tissue per milliliter of lysis buffer (1% sodium dodecylsulfate, 1 mmol/L Na vanadate, and 1 mmol/L of the protease inhibitor phenylmethylsulphonyl fluoride), and insoluble material was removed by means of centrifugation. Protein content was determined by using the bicinchonic acid reagent (Pierce), with bovine serum albumin as a standard. The lysates were mixed with 5x Laemmli buffer at a ratio of 5:1 and boiled, and proteins were electrophoresed under reducing conditions (16 µg per lane), followed by transfer to presoaked nitrocellulose membranes (Hybond-C pure; Amersham Life Science). The membranes were blocked in phosphate-buffered saline/Dulbecco medium (Gibco BRL, Life Technology) with 0.1% Tween and 5% nonfat dry milk, followed by incubation with rabbit polyclonal IB (Santa Cruz sc-371) diluted 1:1000. A goat anti-rabbit (StressGen Biotechnologies) IgG-alkaline phosphatase 1:1000 dilution and an alkaline phosphatase conjugate substrate kit (BioRad Laboratories) were used for visualization.
Statistical analysis
Functional data are given as means ± SEM. Differences in functional recovery were tested by using 2-way analysis of variance (ANOVA) with repeated measures on one factor, taking treatment as an independent factor and time as a dependent factor. The treatment-time interaction in ANOVA refers to the statistical test of whether mean profiles for one group are the same as for the other groups. In the case of significant interaction, simple effects (ie, effects of one factor holding another factor fixed) were examined. Planned comparisons between the groups across factor time were then performed. The P values were thereafter corrected according to the Bonferroni procedure. If the sphericity assumption was not met, the degrees of freedom of the F tests associated with the time factor were reduced by multiplying each degree of freedom by the Greenhouse-Geisser 
value. Normal probability plots were performed to confirm that the underlying model assumptions were met by the data.
Infarct size is presented as box plots with median and quartiles and with whisker plots as minimum and maximum values. Optical densities of EMSA bands are presented either as box plots or as scatterplots. The infarct sizes were approximately normally distributed, and thus comparisons of optical densities and infarct sizes were performed by means of 1-way ANOVA. When significant P values were calculated, intergroup comparisons were performed with the Duncan post hoc test.
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, B). The differences between normoxic control hearts and hearts from hyperoxic animals pretreated with PDTC (group 3) could be due to chance (P > .2). However, pretreatment of normoxic control animals with PDTC improved postischemic recovery of LVDP (P = .03; Figure 2, B). When PDTC was added to the perfusate (group 8), postischemic left ventricular function was not influenced (Figure 3, B).
Left ventricular end-diastolic pressure
With SN50, LVEDP increased during reperfusion of normoxic control hearts (group 1). Sixty minutes of hyperoxia immediately before perfusion (group 2) did not significantly influence postischemic LVEDP (Figure 2, A). The differences between normoxic control hearts (group 1) and hearts from normoxic animals pretreated with SN50 (group 4) or between hearts from hyperoxic animals pretreated with SN50 (group 3) and normoxic control hearts could be due to chance (P > .2). Infusion of SN50 during ischemia and reperfusion (group 7) did not influence postischemic LVEDP (Figure 3, A).
With PDTC, 60 minutes of hyperoxia immediately before perfusion attenuated an increase of LVEDP. Pretreatment with PDTC before exposure to hyperoxia (group 5) did not significantly influence postischemic LVEDP compared with that seen in hyperoxic hearts (group 2; Figure 2, B). The differences between hearts from normoxic animals pretreated with PDTC (group 6) and normoxic control hearts or between hearts from hyperoxic animals pretreated with PDTC (group 5) and normoxic control hearts could be due to chance (P > .2). PDTC added to the perfusate during ischemia and reperfusion (group 8) reduced the increase of LVEDP during reperfusion (P = .004; Figure 3, B).
Left ventricular systolic pressure and heart rate
The differences in LVSP within or between the groups could be due to chance (P > .2, data not shown). In the SN50 study the mean HR immediately before global ischemia was 281 ± 5 beats/min for all groups, whereas in the PDTC study the value was 310 ± 5 beats/min. Both preischemic and postischemic differences within or between the groups could be due to chance (P > .2).
Coronary flow
With SN50, CF was reduced during reperfusion of normoxic control hearts (group 1). Pretreatment with hyperoxia (group 2) inhibited this reduction (P < .001; Figure 2, A). SN50 given before exposure to hyperoxia (group 3) abolished the beneficial effect of hyperoxia (P < .001). The differences between normoxic control hearts and hearts from normoxic animals pretreated with SN50 (group 4) and between normoxic control hearts and hearts from hyperoxic animals pretreated with SN50 (group 3) could be due to chance (P > .2; Figure 2, A). When SN50 was administered to the isolated heart during ischemia and reperfusion (group 7), CF was not influenced (Figure 3, A).
PDTC pretreatment (group 5) abolished the beneficial effect of hyperoxia on CF (P < .001; Figure 2, B). The differences between normoxic control hearts and hearts from hyperoxic animals pretreated with PDTC or between normoxic control hearts and hearts from normoxic control animals pretreated with PDTC could be due to chance (P > .2). Infusion of PDTC to the isolated heart during ischemia and reperfusion (group 8) improved postischemic CF (P = .05; Figure 2, B).
Infarct size
In hearts from normoxic control animals (group 1), 33% ± 3% of total myocardial tissue was calculated as unstained by TTC after 60 minutes of reperfusion. Hyperoxia (Group 2) reduced this area to 19% ± 3% (P = .04; Figure 4, A). Pretreatment with SN50 before exposure to hyperoxia (group 3) inhibited the effect of hyperoxia (35% ± 7%, P = .003). The differences between normoxic control hearts and hearts from hyperoxic animals pretreated with SN50 (group 3) or hearts from normoxic control animals pretreated with SN50 (group 4) could be due to chance (P > .2). Infarct size was profoundly reduced when SN50 was infused during ischemia and reperfusion (group 7, 13% ± 2%, P = .004).
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, B). However, pretreatment of either normoxic control or hyperoxic animals with PDTC (group 6) limited myocardial necrosis compared with that seen in normoxic control hearts (35% ± 2% vs 44% ± 3% [P = .007] and 34% ± 1% vs 44% ± 3% [P = .004]). Administration of PDTC during ischemia and reperfusion (group 8) also limited the necrotic area (29% ± 2%, P < .001; Figure 4, B).
Activation of transcription factors
When hearts were sampled immediately after 60 minutes of hyperoxia (group 2) and compared with normoxic control hearts (group 1), activation of NFB and AP-1 was found in nuclear extracts of all hyperoxic hearts. A representative EMSA of nuclear extracts from 6 hyperoxic and 6 normoxic control hearts with radiolabeled NFB probe is shown in Figure 5, A, where the bands could be supershifted with anti-p50 antibody. The band optical densities were increased by means of hyperoxia (Figure 5, C). When the same samples were incubated with a radiolabeled AP-1 probe, activation of AP-1 was found after 60 minutes of hyperoxia (Figure 5, B and D). In the lungs sampled serially after different durations of hyperoxia, NFB was activated already after 2 minutes and thereafter gradually decreased during 60 minutes of exposure (Figure 6, A). In the hearts activation of NFB could be seen after 2 to 5 minutes of exposure, was thereafter reduced, and increased again at the end of 60 minutes of hyperoxia. The identity of the proteins bound to the probe was verified by means of supershift analysis and cold-probe competition (Figure 6, A).
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B and AP-1 activationB probe is shown in Figure 5, E. Incubation with anti-p50 caused restriction of the probe, and the band could be abolished with cold-probe competition. The NFB inhibitor SN50 administered before exposure to hyperoxia (group 3) reduced activation of the transcription factor. The band optical densities are shown in Figure 5, G. The NFB inhibitor SN50 also reduced the AP-1 band (Figure 5, F and H). When an anti-junD antibody was included, the probe was restricted and abolished by means of cold-probe competition.
NFB during ischemia and reperfusion
The myocardial NFB translocations during Langendorff perfusion, ischemia, and reperfusion are shown in Figure 6, B. In hearts isolated from normoxic control animals (group 1), NFB was activated after 25 minutes of Langendorff perfusion and remained activated during ischemia and early reperfusion. In hearts from hyperoxic animals (group 2), in contrast, a consistently reduced activation of NFB than seen in hearts from control animals was observed. The band identities were verified by means of supershift and cold-probe competition.
IB levels during ischemia and reperfusion
A representative immunoblot of cytoplasmatic proteins after incubation with a rabbit polyclonal antibody against the inducible inhibitory protein IB is shown in Figure 6, C. Hyperoxia increased the bands for IB during stabilization, ischemia, and reperfusion.
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Discussion |
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B and AP-1 were activated in the hearts by means of hyperoxia, and inhibition of NFB activation with 2 different pharmacologic agents abolished the beneficial effects. Hearts from hyperoxic animals had less NFB activation during ischemia and reperfusion. This might be due to an increase of the inducible NFB inhibitory protein IB. Thus we suggest that NFB plays a dual role in the heart. It might play a key role in the myocardial adaptation to ischemia presently induced by hyperoxia, but it also has a detrimental role in hearts not adapted to sustained ischemic insult. When the NFB inhibitor PDTC was infused into the isolated heart during ischemia and reperfusion, the postischemic recovery of myocardial contractile function was improved, whereas PDTC and SN50 both reduced infarct size.
It has previously been demonstrated by us 16 and others 17 that low doses of exogenous reactive oxygen species might protect myocardial function, indicating that moderate oxidative stress is cardioprotective. Normobaric hyperoxia induces oxidative stress in cell cultures. 18 Li and colleagues 19 have demonstrated that NFB is activated by means of hyperoxia in cultured human alveolar epithelial cells. In the present study we found that NFB becomes activated in a time-dependent manner starting in the lungs and rapidly followed by activation in the heart during hyperoxic exposure. In the lungs NFB activation gradually decreased, whereas in the heart it followed a biphasic pattern, with a second peak after 20 to 60 minutes of hyperoxic exposure. At the moment, we do not know how systemic hyperoxia causes activation of cardiac NFB. To inhibit cardiac NFB activation, we used the synthetic peptide SN50, which is a highly specific NFB inhibitor. 20 The present study showed that beneficial functional and anti-infarct effects of hyperoxic exposure were completely blocked with SN50 in isolated rat hearts. Results from EMSA analysis suggest that SN50 did not completely inhibit activation of myocardial NFB. A higher concentration of SN50 might have abolished the activation. Another NFB inhibitor, PDTC, which suppresses NFB activation through inhibiting the reversible release of the inhibitory protein IB, 14 reduced the functional protection and infarct-limiting effects of hyperoxia. PDTC has also been shown to possess antioxidant properties. 21 Pretreatment of normoxic animals with PDTC, but not SN50, before heart isolation attenuated the postischemic depression of myocardial function, indicating that antioxidant properties of PDTC might have been of importance.
Our present findings are in accordance with studies investigating the role for NFB in ischemic preconditioning. Maulik and coworkers 8 demonstrated that ischemic preconditioning of isolated rat hearts induced translocation of NFB, and SN50 inhibited the achieved cardioprotection. Similarly, Morgan and associates 10 inhibited preconditioning in rabbits by using the NFB inhibitor ProDTC. Xuan and associates 9 showed that even delayed cardioprotection by means of preconditioning of the heart was abolished by means of pharmacologic inhibition of NFB.
NFB and AP-1 are activated also during prolonged ischemia and reperfusion of the heart. 22,23 In studies on sustained ischemia-reperfusion injury, NFB activation appears to play a detrimental role because its inhibition with nonsense decoy oligos improves functional recovery and reduces infarction. 11,12 These results are supported by our findings of a moderate reduction of infarction and improvement of postischemic cardiac function when PDTC was administered to control animals before heart isolation. Furthermore, using PDTC or SN50 during perfusion of the isolated heart improved functional recovery and reduced myocardial necrosis after global ischemia. However, the effects of PDTC on postischemic contractile function were more apparent than the effects of SN50 and might have been secondary to its antioxidant effect. Taken together, our data support that activation of NFB in ischemia without previous adaptation is detrimental.
The beneficial effects of NFB activation by means of hyperoxia or preconditioning could be related to anti-inflammatory effects caused by upregulation of the rapidly inducible IB, thereby reducing inflammation during sustained ischemia by inhibiting NFB activation. Hearts from animals subjected to hyperoxia had less NFB activation during Langendorff perfusion, induced global ischemia, and reperfusion than hearts from normoxic control animals. Our findings are in accordance with those in isolated, classic, preconditioned rabbit hearts. 10 Furthermore, the NFB inhibitor IB, which is transcriptionally induced by means of NFB activation, was upregulated in hyperoxic hearts during sustained ischemia. These findings indicate that the benefit of NFB activation during adaptation to ischemia is partly an anti-inflammatory effect caused by upregulation of NFB activation. However, the beneficial effect of hyperoxia could be also due to transcription of an NFB-regulated beneficial gene, 24 but the latter is not investigated in the present study.
In conclusion, the present study demonstrates that in vivo exposure to short-term hyperoxia profoundly protects heart function and preserves cell viability through an NFB-dependent mechanism. In this study the heart was the only organ investigated, but it is likely that the protective effects of hyperoxia are systemic. Theoretically, hyperoxia might increase the endogenous defense in all cell types. Such a concept is in agreement with recent findings, in which hyperoxia reduces wound infections 1 and augments antimicrobial defenses. 2 We speculate that ventilation with a hyperoxic gas might be used in patients to protect any organ or the whole organism, for instance in connection with possible complications accompanying major operations.
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B in cytokine gene regulation. Am J Respir Cell Mol Biol. 1997;17:3-9.B: a pivotal role in asthma and a new target for therapy. Trends Pharmacol Sci. 1997;18:46-50.[Medline]B in tyrosine kinase signaling of p38 MAP kinase regulation of myocardial adaptation to ischaemia. FEBS Lett. 1998;429:365-9.[Medline]B plays an essential role in the late phase of ischemic preconditioning in conscious rabbits. Circ Res. 1999;84:1095-109.B in the cardioadaptive response to ischemia. Ann Thorac Surg. 1999;68:377-82.B binding site prevents myocardial infarction. Nat Med. 1997;3:894-9.[Medline]B binding site. Circulation. 1997;96(suppl II):II280-5.B activation in intact cells. J Exp Med. 1992;175:1181-94.B and AP-1. Cardiovasc Res. 2000;47:49-56.B by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence. J Biol Chem. 1995;270:14255-8.B and activation protein 1 in postischaemic myocardium. FEBS Lett. 1997;401:30-4.[Medline]B during ischemia in perfused rat heart. Am J Physiol. 1999;276:H543-5.This article has been cited by other articles:
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  X. Lu, H. Liu, L. Wang, and S. Schaefer Activation of NF-{kappa}B is a critical element in the antiapoptotic effect of anesthetic preconditioning Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1296 - H1304. [Abstract] [Full Text] [PDF]
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 G. Valen Extracardiac approaches to protecting the heart Eur. J. Cardiothorac. Surg., April 1, 2009; 35(4): 651 - 657. [Abstract] [Full Text] [PDF]
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G. Czibik, Z. Wu, G. P. Berne, M. Tarkka, J. Vaage, J. Laurikka, O. Jarvinen, and G. Valen Human adaptation to ischemia by preconditioning or unstable angina: involvement of nuclear factor kappa B, but not hypoxia-inducible factor 1 alpha in the heart Eur. J. Cardiothorac. Surg., November 1, 2008; 34(5): 976 - 984. [Abstract] [Full Text] [PDF]
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 C. Han, L. Lin, W. Zhang, L. Zhang, S. Lv, Q. Sun, H. Tao, J. H. Zhang, and X. Sun Hyperbaric Oxygen Preconditioning Alleviates Myocardial Ischemic Injury in Rats Experimental Biology and Medicine, November 1, 2008; 233(11): 1448 - 1453. [Abstract] [Full Text] [PDF]
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 S. R. Thom, V. M. Bhopale, D. J. Mancini, and T. N. Milovanova Actin S-Nitrosylation Inhibits Neutrophil {beta}2 Integrin Function J. Biol. Chem., April 18, 2008; 283(16): 10822 - 10834. [Abstract] [Full Text] [PDF]
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M.-L. Kaljusto, K.-O. Stenslokken, T. Mori, A. Panchenko, M.-L. Frantzen, G. Valen, and J. Vaage Preconditioning effects of steroids and hyperoxia on cardiac ischemia-reperfusion injury and vascular reactivity Eur. J. Cardiothorac. Surg., March 1, 2008; 33(3): 355 - 363. [Abstract] [Full Text] [PDF]
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 B. P. Cabigas, J. Su, W. Hutchins, Y. Shi, R. B. Schaefer, R. F. Recinos, V. Nilakantan, E. Kindwall, J. A. Niezgoda, and J. E. Baker Hyperoxic and hyperbaric-induced cardioprotection: Role of nitric oxide synthase 3 Cardiovasc Res, October 1, 2006; 72(1): 143 - 151. [Abstract] [Full Text] [PDF]
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H. Choi, S.-H. Kim, Y.-S. Chun, Y.-S. Cho, J.-W. Park, and M.-S. Kim In vivo hyperoxic preconditioning prevents myocardial infarction by expressing bcl-2. Experimental Biology and Medicine, April 1, 2006; 231(4): 463 - 472. [Abstract] [Full Text] [PDF]
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