© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Unstable angina activates myocardial heat shock protein 72, endothelial nitric oxide synthase, and transcription factors NF
B and AP-1
aCrafoord Laboratory of Experimental Surgery, Karolinska Hospital, S-171 76 Stockholm, Sweden
bCenter for Molecular Medicine, Karolinska Hospital, S-171 76 Stockholm, Sweden
cDepartment of Thoracic Surgery, Karolinska Hospital, S-171 76 Stockholm, Sweden
* Corresponding author. Tel.: +46-8-517-74846; fax: +46-8-517-73557 guro.valen{at}cmm.ki.se
Received 8 November 1999; accepted 8 March 2000
 |
Abstract |
|---|
 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
Objective: Unstable angina may improve the clinical outcome of acute myocardial infarction, but increases the morbidity and mortality of open heart surgery. We hypothetized that unstable angina influences the myocardium, and investigated the expression of the inducible heat shock protein 72 (HSP72), constitutive HSP73, and endothelial nitric oxide synthase (eNOS), and activation of the transcription factors NF
B and AP-1 in cardiac tissue. Methods: Biopsies were taken from the right atrium of 15 patients with unstable and 15 with stable angina undergoing coronary artery bypass grafting. Immunoblotting with monoclonal antibodies against HSP72, HSP73, and eNOS were performed on protein extracts, while nuclear proteins were assessed by electromobility shift assay. Results: When calculating the optical density of the bands, patients with unstable angina had more than twice as much HSP72 and eNOS as stable patients (P<0.005), while HSP73 was similar in both groups. Nuclear translocation of NFB and AP-1 was found in patients with anginal pain shortly before surgery, but not in stable patients or in patients without symptoms for 4 days or more prior to surgery. Conclusions: HSP72 and eNOS, which may be associated with cardioprotection in ischemic preconditioning, are increased in atrial tissue of patients with unstable angina. Activation of NFB and AP-1, which regulate a battery of inflammatory genes, was found in hearts of unstable patients. NFB activation may induce a myocardial proinflammatory state, possibly making the unstable myocardium more susceptible to the inflammation induced by open heart surgery.
KEYWORDS Coronary disease; Endothelial factors; Hypoxia/anoxia; Infection/inflammation; Preconditioning
|
1 Introduction |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
Unstable coronary syndromes are currently believed to be caused by rupture of an atherosclerotic plaque due to local events, which may be of infectious, immunologic, or general inflammatory etiology [1–3]. It is well documented that patients with unstable coronary syndromes have a systemic inflammatory response with increase of the acute phase reactant C-reactive protein, soluble leukocyte adhesion molecules, and markers of leukocyte activation [2,3]. The redox sensitive transcription factor nuclear factor kappa B (NF
B) is activated in peripheral leukocytes from patients with unstable angina [4]. Whether the systemic response of unstable angina is cause or consequence of disease is presently not determined. There is clinical evidence that the myocardium itself is influenced by unstable angina. Patients with unstable angina prior to acute myocardial infarction have improved outcome: reduced mortality, reduced severe congestive heart failure and shock, smaller infarcts as evaluated by CK-MB leakage, and less Q-wave activity than patients with acute infarction of sudden onset [5–7]. The latter phenomenon has been attributed to a preconditioning effect caused by the intermittent ischemia and reperfusion of unstable angina. Paradoxically, patients with unstable coronary syndromes undergoing acute coronary artery bypass grafting have increased morbidity and mortality compared to elective patients [8]. An important feature in the increased risk to the surgical procedure is per- and postoperative pump failure [8]. The different effect of unstable angina in these two situations could be explained by unstable angina triggering both protective and inflammatory substances in the myocardium. In myocardial infarction, the events could favour protection and healing, while in open heart surgery with the local inflammatory response of cardiac ischemia-reperfusion and cardioplegic arrest, as well as the systemic inflammatory response of major surgery, extracorporeal circulation inducing, i.e. endotoxemia and complement activation [9,10], the events could go in favour of increased inflammation and increased myocardial vulnerability.
We hypothesize that unstable angina elicits both protective and detrimental gene programs in the myocardium. Biopsies of right atrial tissue were obtained from patients with unstable and stable coronary artery disease in conjunction with coronary artery bypass surgery. To evaluate a possible activation of gene programs regulating inflammation, the redox sensitive transcription factors activator protein-1 (AP-1) and nuclear factor kappa B (NFB) were investigated by electromobility shift assay (EMSA). The inducible heat shock protein 72, (HSP72), the constitutive HSP73, and endothelial nitric oxide synthase (eNOS) were evaluated by immunoblotting as candidates for possible endogenous cardioprotective agents.
|
2 Methods |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
2.1 Patient population
The study was approved by the Ethics Committee of the Karolinska Hospital and conforms with the principles outlined in the Declaration of Helsinki (Cardiovascular Research 1997;35:2–3). Fifteen consecutive patients with unstable angina and 15 patients with stable angina scheduled for coronary artery bypass grafting (CABG) were investigated. All patients gave informed consent to participate. Unstable patients were defined as rest angina or excertional angina resistant to oral nitroglycerine; upon admission to the coronary care unit transient ischemic ST-segment changes were found; the patients were treated with nitroglycerine i.v. and low molecular weight heparin (Fragmin®), and medical therapy with calcium (4/15) and beta-adrenergic antagonists (15/15) was optimized. When coronary angiography revealed double or triple vessel disease anatomically unsuitable for PTCA combined with persistent symptoms, the patients were scheduled for acute or semi-acute CABG and included in the study. The start of acute symptoms prior to surgery was 9±3 days (mean±S.E.M.). At the time of surgery less than 30% percent of the unstable patients had ongoing symptoms. For EMSA analysis the patients were subgrouped into those with ongoing symptoms at the time of surgery (n=4), those with intermediate symptoms (anginal pain 1–2 days prior to surgery) (n=6), and those who had been without symptoms 3 days or more before surgery (n=5). Stable patients had excertional angina, positive exercise stress-test combined with double or triple vessel disease, and were scheduled for elective CABG. All were treated with beta-adrenergic antagonists and organic nitrates preoperatively, while 4/15 were treated with calcium antagonists. One stable patient had left main stem stenosis. The unstable patients were older than the stable patients (P<0.01) (Table 1). The other preoperative data (ejection fraction, EF), number of previous myocardial infarctions, extent of coronary artery disease, months of angina pectoris prior to surgery) were not statistically different between groups (Table 1). No patient had EF<25%. The main accompanying diseases were diabetes, hypertension, and hyperlipidaemia, and were similarly distributed between stable and unstable patients (Table 1). Two stable and one unstable patient had preoperative paroxysmal supraventricular tachycardia or atrial fibrillation and were treated with digitalis. One stable patient has asthma and was treated with budesonide and salbutamole inhalation aerosol, three unstable patients were dyspeptic and treated with omeprazol, and one unstable patient was treated with the tricyclic antidepressant imipramin.
|
2.2 Operative procedures and tissue sampling
Anesthesia was induced with midazolam and fentanyl and maintained with midazolam, fentanyl, and isoflurane while muscle relaxation was obtained with pancuronium. The patients were ventilated mechanically. After sternotomy, heparin was given to achieve an activated clotting time over 480 s. Arterial cannulation for cardiopulmonary bypass (CPB) was in the ascending aorta, and a two stage venous cannula in the right atrium and the inferior vena cava was used for outflow to the CPB. A biopsy of approximately 0.5x0.5x0.5 cm was cut from the right atrial auricle in conjunction with venous cannulation, and immediately immersed in liquid nitrogen.
CPB was conducted at 34°C with non-pulsatile flow and a membrane oxygenator (Medtronic Cardiopulmonary, Anaheim, CA, USA). Cold, intermittent blood cardioplegia given both ante- and retrogradely was used for myocardial protection. The left internal thoracic artery and the great saphenous vein were employed as grafts in all patients.
2.3 Immunoblotting
Half of the frozen tissue biopsy was homogenized at a ratio of 40 mg tissue/ml lysis buffer [1% SDS, 1 mM Na vanadate, 1 mM protease inhibitor phenylmethylsulphonyl fluoride (PMSF)], and insoluble material removed by centrifugation. Protein content was determined using the bicinchonic acid reagent (Pierce, Rockford, IL, USA) with bovine serum albumin as a standard. The lysates were mixed with 5x Laemmi buffer at a ratio of 5:1, boiled, and proteins were electrophoresed under reducing conditions (1 µg protein/lane for HSP72, 4 µg protein/lane for HSP73, and 34 µg protein/lane for eNOS) followed by transfer to presoaked nitrocellulose membranes (Hybond-C pure; Amersham Life Science). The membranes were blocked in PBS/Dulbecco's (Gibco BRL, Life Technology) with 0.1% Tween and 5% nonfat dry milk followed by incubation with mouse monoclonal anti-HSP72, mouse monoclonal anti-HSP73 (Stress Gen Biotechnologies Corporation) diluted 1/1000, or mouse monoclonal anti-ecNOS (Transduction Laboratories) diluted 1/2500. Goat anti-mouse IgG-alkaline phosphatase (StressGen Biotechnologies) diluted 1/1000 and an alkaline phosphatase conjugate substrate kit (BioRad Laboratories) were used for visualization. Additional gels were stained with Coomasie blue for visualization of the measured protein contents. The bands were scanned into Adobe Photoshop 5.0 (Adobe Systems Inc., San Jose, CA, USA), and optical densities calculated in Tina 2.0 (Strauberhardt, Germany) as a semi-quanitative method.
2.4 Preparation of nuclear extracts
The remaining part of the atrial biopsy was homogenized when frozen in a mikrodismembrator (Braun Biotech Int., GmBH, Germany). Lysis buffer containing 10 mM Hepes (pH 7), 10 mM KCl, 1.5 mM MgCl2, 1 mM PMSF, 0.4% Nonidet P-40, and 50 µl protease inhibitor mix (15 µg/ml leupeptin, 15 µg/ml aprotinin, 1 mM dithiothreitol, and 0.2 mM EDTA) was added before additional homogenization. After incubation on ice, nuclei were collected by centrifugation at 8000xg (4°C) for 1 min. They were washed with 20 mM KCl buffer, centrifuged again, and suspended in 20 mM KCl buffer. An equal part 600 mM KCl was added to the pellet and kept on ice for 30 min to release soluble proteins from the nuclei without inducing membrane lysis. After centrifugation, the supernatant was collected as nuclear extract, and protein content was determined using the bicinchonic acid reagent (Pierce).
2.5 Electrophoretic mobility shift assay
Nuclear extracts (16 µg protein/lane) were preincubated for 10 min in binding buffer (20 mM Hepes pH 7.9, 5% glycerol, 5 mM MgCl2, 0.5 mM EDTA, and 1 mM dithiothreitol) on ice, followed by 30 min incubation at room temperature with 50 000 cpm of 32P-labelled 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 Promega). 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, Santa Cruz, CA, USA) were incubated with the binding buffer for 15 min prior to adding the radiolabelled probe. For competition analysis, unlabelled probe in 100-fold excess was added prior to radiolabelled probe.
2.6 Statistics
Student's t-test was used for evaluation between groups. P<0.05 was considered significant. Values are presented as mean±S.E.M.
|
3 Results |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
3.1 Clinical course
Both patient groups received the same number of distal anastomoses, and did not have a significantly different length of stay in the intensive care unit (Table 1). There was no mortality in either group. Two of the unstable patients needed pharmacological inotropic support when weaning off bypass and during the first hours in the ICU, while none of the stable patients needed this. There were no perioperative myocardial infarctions. Minor postoperative events such as atrial fibrillation or conduction disturbances (AV-block) occurred in four unstable and five stable patients. One patient in each group had a postoperative lower urinary tract infection. One stable patient was treated out-hospital for infection of the leg wound, and one of the unstable patients was treated in-hospital on suspicion of septic pericarditis appearing 1 week postoperatively (never verified). Otherwise, the patients had uneventful postoperative recoveries.
3.2 Inducible heat shock protein (HSP72)
When protein extracts from the human atrial biopsies were incubated with mouse monoclonal anti-HSP72 after electrophoretic separation, a band of 72 kDa appeared on the membranes. A representative immunoblot of six stable and seven unstable patients is shown in Fig. 1a. When calculating the optical density of immunoblot bands in all 30 patients, the band density was highest in patients with unstable angina (Fig. 1c).
|
3.3 Constitutive heat shock protein (HSP73)
When the cardiac protein extracts were incubated with a mouse monoclonal antibody against HSP73, a band of 73 kDa appeared. An immunoblot with bands of seven stable and seven unstable patients is shown in Fig. 1b. When calculating optical densities of the bands of all patients, no significant difference was found between cardiac protein extracts (Fig. 1d).
3.4 Endothelial nitric oxide synthase (eNOS)
A typical immunoblot of cardiac proteins extracts from six stable and six unstable patients after incubation with a mouse monoclonal anti-eNOS antibody is shown in Fig. 2a. When the protein extracts were stained with coomasie blue, the same amount of protein per lane was visualized (Fig. 2b). When evaluating all 30 patients, the mean optical density of the 140-kDa eNOS band was higher in patients with unstable angina (Fig. 2c).
|
3.5 Activation of transcription factors
None of the unstable patients had activation of NF
B or AP-1 (not shown). In the group with unstable angina, activation of transcription factors was not consistently found (not shown). However, there was a correspondence between symptoms and activation of transcription factors. In Fig. 3a, activation of NFB in three patients with stable angina (SA), three unstable patients with intermediate symptoms (anginal pain 1–2 days before surgery, UA-1), and three unstable patients with symptoms at the time of surgery (UA-2) is shown. NFB was activated in atrial tissue of unstable patients, as evidenced by increased retardation of the DNA probe containing the NFB motif (Fig. 3a). The identity of the proteins bound to the probe were determined by supershift analysis and cold probe competition (Fig. 3b). An antibody specific for the p50 subunits of the NFB heterodimer caused retardation of the mobility of the DNA probe, while the band disappeared when a cold probe was employed, further identifying the band as NFB. A similar analysis of AP-1 is shown in Fig. 4a, where the same patient samples as shown in Fig. 4a and b were incubated with a radiolabelled DNA probe containing the AP-1 motif, demonstrating AP-1 activation in cardiac tissue from unstable patients with recent or ongoing symptoms (Fig. 4a). An antibody specific for the c-jun subunit of AP-1 caused only a small retardation of the DNA probe (Fig. 4b). Competitive inhibition with cold probe extinguished the AP-1 bands (Fig. 4b).
|
|
|
4 Discussion |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
The main findings of the present study were that right atrial tissue of patients with unstable angina contained more inducible heat shock protein 72 and endothelial nitric oxide synthase than the myocardium of patients with stable angina. Experimental evidence suggests that these proteins are cardioprotective [11–15]. The redox sensitive transcription factors NF
B and AP-1 were activated in unstable patients with recent or ongoing symptoms. NFB alone or in cooperation with AP-1 regulate a battery of inflammatory genes, including proinflammatory cytokines, chemokines, leukocyte adhesion molecules, inducible nitric oxide synthase, and inducible cyclo-oxygenase [16,17]. Their activation in atrial tissue of patients with unstable angina may be a useful switch for tissue response of inflammation and repair. Activation of NFB has recently been suggested to play a part in intracellular signalling in ischemic preconditioning, although inhibition of NFB activation during postischemic reperfusion protects the heart [18–20]. Some papers indicate that unstable angina prior to onset of acute myocardial infarction improves the clinical outcome for these patients, which has been attributed to a preconditioning effect of the intermittent ischemia and reperfusion of unstable angina [5–7]. Short episodes of ischemia and reperfusion prior to a sustained ischemic event — ischemic preconditioning — reduce infarct size and improve cardiac function in experimental studies both as an immediate and a delayed effect [21,22]. The trigger(s) and intracellular signalling systems of preconditioning are not fully clarified, nor are the secondary mediators of myocardial protection [21,22]. Of the suggested mediators of delayed preconditioning are heat shock proteins 70 (HSP70) [11] and nitric oxide synthase [15]. The HSP70 family consists of the inducible HSP72 and the constitutive HSP73, which are involved in protein traffic and folding, translocation of proteins across membranes, and gene regulation [11–13]. HSP70 may have cardioprotective properties. Induction of HSP70 by hyperthermia or ischemic preconditioning reduces infarct size and improves cardiac function, and transgenic mice expressing high levels of HSP70 are protected against ischemia–reperfusion injury [11–13]. However, increased expression of HSP70 is not consistently associated with myocardial protection [23].
Heat shock proteins are regulated by their own transcription factors, and are induced by AP-1 or NFB [13]. Evidence suggests that HSP70 may modulate AP-1 and NFB DNA binding activity [24,25], perhaps explaining some of their possible antiinflammatory and cardioprotective properties. Downregulation of activated transcription factors by HSP70 may explain why these were not detectable in hearts of patients without symptoms for 3 days or more prior to surgery.
Endothelial NOS regulates the constitutive production of nitric oxide (NO). In addition to its vasodilatory action, evidence suggests that NO may have antiarrhythmic, antiinflammatory, antithrombotic, and a possible positive inotropic effect [14,15,26–28]. Experimental studies suggest that NO has cardioprotective actions, although NO overproduction may be associated with peroxynitrate formation. Thus, increased expression of eNOS may be beneficial in the hearts of patients with unstable angina. Although referred to as a constitutive enzyme, eNOS can be upregulated by a number of stimuli, and its promoter region contains recognition sites for a number of transcription factors, among them AP-1 [29]. eNOS is also regulated through a shear stress element, which may have contributed to its increase in unstable patients.
Prior to surgery the only known differences between our patient groups were instability and higher age in the unstable group. Age does not increase inducible HSP70; on the contrary, HSP72 induction decreases with age, and this reduced response has been suggested as a common phenomenon underlying the aging process [30]. In age-matched patients, the difference in HSP72 induction might have been even higher. Similarly, there is no evidence that eNOS expression increases with age. Loss of eNOS expression and NO production is observed in human atherosclerosis [31], and as atherosclerosis is a disease progressing with age the increased eNOS in the unstable patients is likely to be due to the instability.
Although unstable angina protects myocardial function and necrosis against acute myocardial infarction, possibly through increased myocardial expression of HSP72 and eNOS as shown in this study, instability is detrimental before cardiac surgery [8]. The present study is too small to evaluate clinical outcome. Open heart surgery with cardiopulmonary bypass represents a massive inflammatory trauma; major surgery is performed, which in itself induces an inflammatory response. The heart is subjected to a local inflammatory response induced by ischemia and reperfusion during suturing of the distal anastomoses, and the foreign surfaces of the CPB activates blood components [9,10]. Systemic increases of proinflammatory cytokines, soluble leukocyte adhesion molecules, neutrophil activation, complement activation, and endotoxemia are among the events occurring during CPB [9,10]. We demonstrate in the present study that unstable angina induces an inflammatory process in the heart through transcriptional activation. When the unstable heart, which is in a proinflammatory state, is exposed to open heart surgery, it is possible that a more severe inflammatory process is turned on. In support of this, a study from our group investigating the inflammatory response to cardioplegia and reperfusion in patients with stable and unstable angina, showed that patients with unstable angina had increased gene expression of E-selectin, eNOS, TNF
, IL-1β, and a larger decrease of endothelin-1 during reperfusion than stable patients [32].
In the present study atrial biopsies were analysed, although the left ventricle is the tissue of highest interest for cardiac function. This limitation of the study is due to the fact that for ethical reasons left ventricular biopsies large enough to perform protein extractions for the methods employed are unobtainable. Possibly findings would be different in different chambers of the heart. We speculate that the atrium may be representative of the whole myocardium on rationale of the recently discovered whole-body events of remote preconditioning: occlusion and reperfusion of other organs such as kidney, intestine, and limbs protects the heart against subsequent ischemia [33], while preconditioning of the heart protects the lungs against reperfusion injury (manuscript in preparation). These findings may indicate that ischemia and reperfusion of any organ will elicit systemic events which may trigger protection of any organ. The present findings in atrial tissue may support this possibility.
In summary, patients with unstable angina had increased cardiac contents of the inducible HSP72 and eNOS, but not of the constitutive HSP73. This increase may explain a possible preconditioning effect of unstable angina. Patients with angina shortly before surgery had atrial activation of the transcription factors NFB and AP-1, which regulate a battery of inflammatory genes. A myocardial proinflammatory state may reduce tolerance to the inflammation induced by cardiac surgery, and thus contribute to understanding why unstable angina is a risk factor before open heart surgery.
Time for primary review 29 days.
|
Acknowledgements |
|---|
The work has been supported by grants from the Swedish Medical Research Council (6816, 11235 and 12665), The Swedish Heart-Lung Foundation, The Foundations Fredrik o Ingrid Thurings, Tore Nilssons, Åke Wibergs, Harald o Greta Jeanssons, Familien Janne Elgquist, Sigurd and Elsa Goljes Memory, and the Karolinska Institute.
|
References |
|---|
|
TopAbstract1 Introduction2 Methods3 Results4 DiscussionReferences |
|---|
- Libby P. Molecular basis of the acute coronary syndromes. Circulation (1995) 91:2844–2850.
[Free Full Text] - Mehta J.L., Saldeen T.G.P., Rand K. Interactive role of infection, inflammation and traditional risk factors in atherosclerosis and coronary artery disease. J Am Coll Cardiol (1998) 31:1217–1225.
[Abstract/Free Full Text] - Crea F., Biasucci L.M., Buffon A., et al. Role of inflammation in the pathogenesis of unstable coronary artery disease. Am J Cardiol (1997) 80:10E–16E.[CrossRef][Medline]
- Ritchie M.E. Nuclear factor-B is selectively and markedly activated in humans with unstable angina. Circulation (1998) 98:1707–1713.
[Abstract/Free Full Text] - Kloner R.A., Shook T., Przyklenk K., et al. Previous angina alters in-hospital outcome in TIMI. 4. A clinical correlate to preconditioning? Circulation (1995) 91:37–47.
[Abstract/Free Full Text] - Hirai T., Fujita M., Yamanishi K., Ohno A., Miwa K., Sasayama S. Significance of preinfarction angina for preservation of left ventricular function in acute myocardial infarction. Am Heart J (1993) 124:19–23.[CrossRef][Web of Science]
- Ottani F., Galvani M., Ferrini D., et al. Ischemic preconditioning: prodromal angina limits myocardial infarct size. J Am Coll Cardiol (1993) 21:149A.
- Iyer V.S., Russell W.J., Leppard P., Craddock D. Mortality and myocardial infarction after coronary artery surgery. Med J Aust (1993) 159:166–170.[Web of Science][Medline]
- Hill G.E. Cardiopulmonary bypass-induced inflammation: Is it important? J Thorac Cardiovasc Anesth (1998) 12:21–25.
- Royston D. The inflammatory response and extracorporeal circulation. J Cardiothorac Vasc Anest (1997) 11:341–354.[CrossRef][Web of Science][Medline]
- Marber M.S., Latchman D.S., Walker J.M., Yellon D.M. Cardiac stress protein elevation 24 h after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation (1993) 88:1264–1272.
[Abstract/Free Full Text] - Leppä S., Sistonen L. Heat shock response — pathophysiological implications. Ann Med (1997) 29:73–78.[Web of Science][Medline]
- Morimoto R.I., Kline M.P., Bimston D.N., Cotto J.J. The heat shock response: regulation and function of heat-shock proteins and molecular chaperones. Essays Biochem (1997) 32:17–29.[Web of Science][Medline]
- Parrat J. Endogenous myocardial protective (antiarrhythmic) substances. Cardiovasc Res (1993) 27:693–702.
[Free Full Text] - Bolli R., Manchikalapudi S., Tang X.-L., et al. The protective effect of late preconditioning against myocardial stunning in conscious rabbits is mediated by nitric oxide synthase. Circ Res (1997) 81:1094–1107.
[Abstract/Free Full Text] - Barnes P.J., Adcock I.M. NFB: a pivotal role in asthma and a new target for therapy. Trends Pharmacol Sci (1997) 18:46–50.[Medline]
- Muller J.M., Rupec R.A., Baeuerle P.A. Study of gene regulation by NFkB and AP-1 in response to reactive oxygen intermediates. Methods (1997) 11:301–312.[CrossRef][Web of Science][Medline]
- Xuan Y.-T., Tang X.-L., Banerjee S., et al. Nuclear factor-kB plays an essential role in the late phase of ischemic preconditioning in conscious rabbits. Circ Res (1999) 84:1095–1109.
[Abstract/Free Full Text] - Maulik N., Sato M., Price B.D., Das D.K. An essential role of NFkB in tyrosine kinase signaling of p38 MAP kinase regulation of myocardial adaptation to ischaemia. FEBS Lett (1998) 429:365–369.[CrossRef][Web of Science][Medline]
- Morishita R., Sugimoto T., Aoki M., et al. In vivo transfection of cis element ‘decoy’ against nuclear factor-kB binding site prevents myocardial infarction. Nat Med (1997) 3(8):894–899.[CrossRef][Web of Science][Medline]
- Jenkins D.P., Steare S.E., Yellon D.M. Preconditioning the human myocardium: Recent advances and aspirations for the development of a new means of cardioprotection in clinical practice. Cardiovasc Drugs Ther (1995) 9:739–747.[CrossRef][Web of Science][Medline]
- Downey J.M., Cohen M.V. Signal transduction in ischemic preconditioning. Adv Exp Med Biol (1997) 430:39–55.[Web of Science][Medline]
- Qian Y.Z., Bernardo N.L., Nayeem M.A., Chelliah J., Kukreja R.C. Induction of 72-kDa heat shock protein does not produce second window of ischemic preconditioning in rat heart. Am J Physiol (1999) 276:H224–234.[Web of Science][Medline]
- Carter D.A. Modulation of cellular AP-1 DNA binding activity by heat shock proteins. FEBS Lett (1997) 416:81–85.[CrossRef][Web of Science][Medline]
- Vayssier M., Favatier F., Pinot F., Bachelet M., Polla B.S. Tobacco smoke induces coordinate activation of HSF and inhibition of NFkappaB in human monocytes: effects on TNFalpha release. Biochem Biophys Res Commun (1998) 252:249–256.[CrossRef][Web of Science][Medline]
- Li X.-S., Uriuda Y., Wang Q.-D., Sjöquist P.-O., Norlander R., Pernow J. Role of L-arginine in preventing myocardial and endothelial injury following ischemia–reperfusion injury in the isolated rat heart. Acta Physiol Scand (1996) 156:37–44.[CrossRef][Web of Science][Medline]
- Valen G., Skjelbakken T., Vaage J. The role of nitric oxide in the cardiac effects of hydrogen peroxide. Mol Cell Biochem (1996) 159:7–14.[Web of Science][Medline]
- Yan Z.-Q., Yokota T., Zhang W., Hansson G. Expression of inducible nitric oxide synthase inhibits platelet adhesion and restores blood flow in the injured artery. Circ Res (1996) 79:38–44.
[Abstract/Free Full Text] - Försterman U., Boissel J.-P., Kleinert H. Expressional control of the ‘constitutive’ isoforms of nitric oxide synthase (NOSI and NOSIII). FASEB J (1998) 12:790.
- Gutsman-Conrad A., Heydari A.R., You S., Richardson A. The expression of heat shock protein 70 decreases with cellular senescence in vitro and in cells derived from young and old human subjects. Exp Cell Res (1998) 241:404–413.[CrossRef][Web of Science][Medline]
- Oemar B.S., Tshudi M.R., Godoy N., Brovkovich V., Malinski T., Luscher T.F. Reduced endothelial nitric oxide synthase expression and production in huna atherosclerosis. Circulation (1998) 97:2494–2498.
[Abstract/Free Full Text] - Valen G, Paulsson G, Vaage J, Hansson GK. Induction of inflammatory mediators during reperfusion of the human heart. Ann Thorac Surg 2000; in press.
- de Zeeuw S., van den Doel M., Duncker D.J., Verdouw P.D. Heart in stress. Das D.K., ed. (1999) 874. New York Academy of Science. 178–191.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. Valen Extracardiac approaches to protecting the heart Eur. J. Cardiothorac. Surg., April 1, 2009; 35(4): 651 - 657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 M. Brown, M. McGuinness, T. Wright, X. Ren, Y. Wang, G. P. Boivin, H. Hahn, A. M. Feldman, and W. K. Jones Cardiac-specific blockade of NF-{kappa}B in cardiac pathophysiology: differences between acute and chronic stimuli in vivo Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H466 - H476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Chao, Y. Shen, X. Zhu, H. Zhao, M. Novikov, U. Schmidt, and A. Rosenzweig Lipopolysaccharide Improves Cardiomyocyte Survival and Function after Serum Deprivation J. Biol. Chem., June 10, 2005; 280(23): 21997 - 22005. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Vaage INVITED COMMENTARY Ann. Thorac. Surg., March 1, 2005; 79(3): 871 - 871. [Full Text] [PDF]
|
|
|
|
 |
|
 B Dybdahl, S A Slordahl, A Waage, P Kierulf, T Espevik, and A Sundan Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction Heart, March 1, 2005; 91(3): 299 - 304. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Goren, J. Cuenca, P. Martin-Sanz, and L. Bosca Attenuation of NF-{kappa}B signalling in rat cardiomyocytes at birth restricts the induction of inflammatory genes Cardiovasc Res, November 1, 2004; 64(2): 289 - 297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Morimoto, Y. Kurahashi, K. Shintani-Ishida, N. Kawamura, M. Miyashita, M. Uji, N. Tan, and K.-i. Yoshida Estrogen replacement suppresses stress-induced cardiovascular responses in ovariectomized rats Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H1950 - H1956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vogt, I. Portig, B. Kusch, S. Pankuweit, A. S. Sirat, D. Troitzsch, B. Maisch, and R. Moosdorf Detection of anti-hsp70 immunoglobulin G antibodies indicates better outcome in coronary artery bypass grafting patients suffering from severe preoperative angina Ann. Thorac. Surg., September 1, 2004; 78(3): 883 - 889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Thiemermann Inhibition of the activation of nuclear factor kappa B to reduce myocardial reperfusion injury and infarct size Cardiovasc Res, July 1, 2004; 63(1): 8 - 10. [Full Text] [PDF]
|
|
|
|
|
|
B. Zingarelli, P. W. Hake, M. O'Connor, A. Denenberg, H. R. Wong, S. Kong, and B. J. Aronow Differential regulation of activator protein-1 and heat shock factor-1 in myocardial ischemia and reperfusion injury: role of poly(ADP-ribose) polymerase-1 Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1408 - H1415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Monaco and E. Paleolog Nuclear factor {kappa}B: a potential therapeutic target in atherosclerosis and thrombosis Cardiovasc Res, March 1, 2004; 61(4): 671 - 682. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. G. Neri Serneri, M. Boddi, P. A. Modesti, I. Cecioni, M. Coppo, M. L. Papa, T. Toscano, A. Marullo, and M. Chiavarelli Immunomediated and Ischemia-Independent Inflammation of Coronary Microvessels in Unstable Angina Circ. Res., June 27, 2003; 92(12): 1359 - 1366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Tahepold, J. Vaage, J. Starkopf, and G. Valen Hyperoxia elicits myocardial protection through a nuclear factor {kappa}B-dependent mechanism in the rat heart J. Thorac. Cardiovasc. Surg., March 1, 2003; 125(3): 650 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tokuno, K. Hinokiyama, K. Tokuno, C. Lowbeer, L.-O. Hansson, and G. Valen Spontaneous Ischemic Events in the Brain and Heart Adapt the Hearts of Severely Atherosclerotic Mice to Ischemia Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 995 - 1001. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. ZINGARELLI, P. W. HAKE, Z. YANG, M. O'CONNOR, A. DENENBERG, and H. R. WONG Absence of inducible nitric oxide synthase modulates early reperfusion-induced NF-{kappa}B and AP-1 activation and enhances myocardial damage FASEB J, March 1, 2002; 16(3): 327 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S Latchman Heat shock proteins and cardiac protection Cardiovasc Res, September 1, 2001; 51(4): 637 - 646. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Valen, Z.-q. Yan, and G.o. K. Hansson Nuclear factor kappa-B and the heart J. Am. Coll. Cardiol., August 1, 2001; 38(2): 307 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Valen, G. Paulsson, and J. Vaage Induction of inflammatory mediators during reperfusion of the human heart Ann. Thorac. Surg., January 1, 2001; 71(1): 226 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Dybdahl, A. Wahba, E. Lien, T. H. Flo, A. Waage, N. Qureshi, O. F.M. Sellevold, T. Espevik, and A. Sundan Inflammatory Response After Open Heart Surgery: Release of Heat-Shock Protein 70 and Signaling Through Toll-Like Receptor-4 Circulation, February 12, 2002; 105(6): 685 - 690. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||