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Right arrow Cardiac - physiology
Right arrow Myocardial protection

Eur J Cardiothorac Surg 2004;26:968-973
© 2004 Elsevier Science NL

Myocardial protection by remote preconditioning: the role of nuclear factor kappa-B p105 and inducible nitric oxide synthase

Guohu Lia, Fausto Labrutoa,*, Allan Sirsjöb, Fei Chena, Jarle Vaagec, Guro Valena

a Crafoord Laboratory for Experimental Surgery L6.00, Karolinska Hospital, S-17176 Stockholm, Sweden
b Center of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden
c Department of Thoracic Surgery, Karolinska Hospital, Stockholm, Sweden

Received 19 April 2004; received in revised form 3 June 2004; accepted 17 June 2004.

* Corresponding author. Tel.: +46-8-51773560; fax: +46-8-51773557. (E-mail: lampo18{at}yahoo.com).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: Adaptation to ischemia by brief episodes of ischemia and reperfusion (preconditioning) of the heart protects the heart against sustained ischemia, where the transcription factor nuclear factor kappa-B (NF{kappa}B) appears crucial for the protection. Preconditioning of the heart may even be evoked by brief episodes of ischemia and reperfusion in other organs. The present study investigates a possible role for NF{kappa}B and inducible nitric oxide synthase (iNOS) in adaption to ischemia by remote, delayed protection. Methods: Mice (wild-types, or with targeted deletions of the NF{kappa}B p105 or the iNOS gene) were subjected to cycles of occlusion and reperfusion of both hind limbs, and 24h later their hearts were isolated and Langendorff-perfused with induced global ischemia and reperfusion. Infarct size was measured. Skeletal muscles from ischemized limbs as well as hearts were also collected for polymerase chain reaction (PCR) and electromobility shift assay (EMSA). Results: Hind limb preconditioning protected left ventricular function and reduced infarct size during reperfusion in wild-type mice. Nuclear translocation of NF{kappa}B was detected in both heart and preconditioned skeletal muscle 1–2h after the preconditioning episodes (EMSA); while cardiac mRNA for iNOS gradually increased in a 24-h time course after hind limb preconditioning (real-time PCR). When hind limbs of mice with targeted deletions for the p105 subunit of NF{kappa}B or the iNOS gene were preconditioned, no beneficial effect was observed in the heart. Conclusions: Delayed cardioprotection induced by hind limb preconditioning involves signaling through NF{kappa}B and iNOS.


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Ischemic preconditioning of the heart profoundly protects cell viability when the adaption takes place less than 2h before the sustained ischemia (classic preconditioning), or when the sustained ischemia is 24–72h after the preconditioning episode (delayed preconditioning). A preconditioning-like myocardial protection can be evoked by systemic stimuli such as lipopolysaccharide, hypoxia, hyperoxia, and nitric oxide [1–3]. It has also become evident that short episodes of ischemia and reperfusion of other organs such as mesenterium, kidney, or hind limbs will protect the heart (remote preconditioning) [1,4]. The perspective of preconditioning research is to find the underlying mechanism of action, and to pharmacologically exploit this in patients for increased myocardial protection.

Mechanisms underlying delayed preconditioning of the heart are the most well studied. Short episodes of ischemia and reperfusion lead to release of trigger substances such as nitric oxide, low doses of reactive oxygen intermediates, adenosine, bradykinin, and/or prostacyclin [3,5]. The triggers may cause activation of kinase cascades where protein kinase C, and probably downstream tyrosine kinase and members of the MAP kinase cascade are important for signaling [6,7]. Protein kinases may activate transcription factors, of which particularly nuclear factor kappa-B (NF{kappa}B) has been investigated in both classic and delayed models in the heart [8,9]. NF{kappa}B is a redox sensitive transcription factor regulating a battery of inflammatory genes such as inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase. The NF{kappa}B family consists of the members p50, p52, p65 (RelA), c-Rel, and RelB which form various homo- and heterodimers, where the most common active form is the p50 or p52/RelA heterodimer. p105 is a precursor to p50 [10]. NF{kappa}B dimers reside in the cytoplasm in an inactive form bound to inhibitory proteins known as I{kappa}B, which are phosphorylated in response to diverse stimuli. The phosphorylated I{kappa}Bs are then ubiquitinated and proteolytically degraded. This process activates NF{kappa}B, which translocates to the nucleus and binds to promoter or enhancer regions of specific genes, initiating transcription.

NF{kappa}B is translocated to the nucleus in the preconditioned heart, and pharmacological blocking of its translocation inhibits preconditioning [8,9]. The beneficial effect of NF{kappa}B in this context may be through upregulation of a beneficial gene, where inducible cyclooxygenase [11], manganese superoxide dismutase, as well as iNOS [12] are implicated as mediators of infarct size reduction afforded by delayed ischemic preconditioning of the heart. Another possibility is that NF{kappa}B activation during the brief ischemic episodes induces an inhibition of NF{kappa}B activation during sustained ischemia through increased of I{kappa}B [13]. It is also possible that the apoptosis limiting effect of NF{kappa}B activation is important for the protection afforded [14].

The mechanisms by which remote preconditioning protects the heart are less well understood. The target of the present study was to investigate the role of NF{kappa}B and iNOS in a mouse model of remote, delayed preconditioning induced by hind limb occlusion 24h prior to heart isolation and Langendorff-perfusion with induced global ischemia and reperfusion. Mice with targeted deletions of the NF{kappa}B p105 subunit, or the iNOS gene were employed for this purpose and compared with wild-types.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1. Animals
The study was performed in accordance with the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Strasbourg 1985), and was approved by the Animal Ethics Committee of Northern Stockholm (Stockholms Norra Djurforsöksetiska Nämnd). Female mice with homozygously targeted deletion of the NF{kappa}B p105 gene, as well female homozygous iNOS knockout mice were purchased from The Jackson Laboratory (Maine, USA, B6, 129P-Nfkb1<tm1Bal> and B6, 129P-Nos2<tm1lau>) with wild-type age-matched females as controls (B6, 129PF1/J-A<A-J/A<W>FX or F1). The mice were approximately 4 months old when employed for experiments, and were without any phenotypical or developmental deviations.

2.2. Hind limb preconditioning and isolated heart perfusion
The mice were anaesthetized intraperitoneally with pentobarbital (60mg/kg), and a bilateral external tourniquet was applied around the upper hind limb joint for 5min followed by 5min reperfusion for a total of 6 cycles. Twenty-four hours after preconditioning or sham treatment the mice were re-anaesthetized, and hearts were isolated and Langendorff-perfused. Retrograde perfusion with gassed (5% CO2, 95% O2) Krebs–Henseleit buffer was performed at a constant pressure of 55mmHg. Left ventricular pressures, coronary flow, and arrhythmias were registered. The data were collected by a continuous data collection system.

2.3. Protocol
Hearts were stabilized for 25min, and the balloon volume adjusted to have a LVEDP of 5mmHg. Forty minutes of global ischemia was induced by clamping the inflow tubing followed by 60min of reperfusion. Wild-type mice with hind limb preconditioning, wild-type sham treated, NF{kappa}B p105 knockouts with hind limb preconditioning, NF{kappa}B sham treated, and iNOS knockouts either preconditioned or sham treated (n=7 of each) were investigated for infarct size and hemodynamics. Additional tissue was sampled for supplementary analysis.

2.4. Measurement of infarct size
At the end of reperfusion, hearts were perfused with 1% triphenyltetrazolium chloride solution (TTC, Sigma Chemical Co., St Louis, MO), fixed in 4% formaldehyde and cut into 1mm transverse slices. Digitized images were obtained by a magnified video system (LEICA Qwin, Leica Imaging Systems Ltd, Cambridge, England), and the percentage of infarcted area calculated semi-automatically (Adobe PhotoShop 5.0, Adobe, San Jose, CA).

2.5. Electromobility shift assay
Samples of skeletal muscle and hearts were collected before start of preconditioning, and 1 and 2h after later. Hearts were collected after 25min perfusion, 40min ischemia, and 20min reperfusion (triplicate samples at all time points and groups). Nuclear proteins were extracted and incubated with a 32P labeled probe containing the NF{kappa}B binding site (Promega) as previously described in detail [13]. DNA-protein complexes were electrophoresed on a 4% polyacrylamide gel. For supershift analysis, a rabbit polyclonal anti-p50 antibody or a rabbit polyclonal anti-p65 antibody (both Santa Cruz Biotechnology, Santa Cruz, CA) were employed. For competition analysis, unlabelled probe in 25- or 50-fold excess was added prior to radiolabeled probe (results not shown).

2.6. Real-time PCR
Hearts from preconditioned wild-types were collected before limb ischemia, and 3, 6, 12, 18, and 24h after preconditioning (two animals at each time point) for real-time polymerase chain reaction (PCR) analysis of iNOS. Total RNA was extracted with an RNA isolation kit (UltraspecTM RNA, Biotecx, Houston, TX) and reversely transcribed. cDNA was amplified by real-time PCR with 1x TaqMan Buffer (PE Biosystem, Foster City, CA). For the amplification of ß-actin the forward primer 5'-AGA GGG AAA TCG TGC GTG AC-3', reverse primer 5'-CAA TAG TGA TGA CCT GGC CGT-3' and probe 5'-CAC TGC CGC ATC CTC TTC CTC CC-3' were used. For the amplification of iNOS, the forward primer 5'-CAG CTG GGC TGT ACA AAC CTT-3', reverse primer 5'-CAT TGG AAG TGA AGC GTT TCG-3', and probe 5'-CGG GCA GCC TGT GAG ACC TTT GA-3' (PE Biosystems) were used. Each sample was analyzed in duplicates using ABI Prism 7700 Sequence Detector (PE Biosystems) and correlated to a standard curve. The reactions were performed in MicroAmp Optical 96-Well Reaction Plates (PE Biosystems).

2.7. Statistical analysis
Data are presented as mean±SEM. Repeated measure ANOVA was employed for evaluation of hemodynamics, with a Scheffe's post hoc test. Infarct size was compared by unpaired t test. P<0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. NF{kappa}B translocation after limb preconditioning
When nuclear protein extracts from heart and hind limb skeletal muscle were analyzed with EMSA, no activation of NF{kappa}B was apparent prior to preconditioning (Fig. 1A). However, 1 and 2h after end of limb preconditioning a nuclear factor binding specifically to a NF{kappa}B consensus sequence appeared in both heart and skeletal muscle. The composition of the protein–DNA complex was analyzed by adding antibodies to the p65 or p50 subunits of the NF{kappa}B family. The p50, but not the p65, antibody caused a retardation of the probe (Fig. 1A).



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  		Fig. 1. Upper panel: A representative electromobility shift assay with a radiolabeled NF{kappa}B probe of nuclear protein extracts obtained from heart (H) or skeletal muscle (M) of mice subjected to bilateral hind limb preconditioning (6 cycles of 5min occlusion through an external tourniquet followed by 5min reperfusion). Samples taken before preconditioning (0), at the end of the procedure (1) and 2h after start of the procedure (2) of wild-type mice are shown. Sample M2 was supershifted when an antibody to the p50 subunit of NF{kappa}B was added, while a p65 antibody did not retard the labeled DNA-complex. The last lane shows sample H2 with the p50 antibody. Lower Panel: mRNA was extracted from hearts of wild-type mice before limb preconditioning as described above, and serially after start of preconditioning. The mRNA was amplified with real-time PCR with primers for iNOS and ß-actin as a reference gene. The ratio between mRNA for iNOS and ß-actin is shown as individual values from two experiments.

 
3.2. Cardiac iNOS mRNA induction
mRNA was extracted from hearts serially after preconditioning the hind limbs, and the synthesized cDNA was amplified with real-time PCR using ß-actin as a reference gene. The ratio between iNOS and ß-actin increased gradually after preconditioning the hind limbs, reaching the highest level 24h after the preconditioning episode, corresponding to time of Langendorff-perfusion (Fig. 1B).

3.3. Heart function
3.3.1. Left ventricular pressures
Left ventricular developed pressure (LVDP) decreased during reperfusion after 40min global ischemia. Preconditioning the hind limbs 24h prior to heart isolation attenuated this decrease (P<0.05) (Fig. 2). In mice with targeted gene deletions of the p105 subunit of NF{kappa}B, the depression of LVDP during reperfusion was attenuated compared with wild-types (P<0.05). However, no beneficial effect of preconditioning could be found (Fig. 2). In analogy, mice with targeted deletions of the iNOS gene had less depression of LVDP during reperfusion than wild-types (P<0.05), but no beneficial effect of preconditioning was apparent (Fig. 2).



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  		Fig. 2. Left ventricular developed (LVDP) and end-diastolic (LVEDP) pressures in Langendorff-perfused mice hearts isolated 24h after sham treatment (C) or limb preconditioning (LPC) as described in legend to Fig. 1, and subjected to 40min of global ischemia followed by reperfusion. Mice were either wild-type (B6, 129), deleted for the p105 subunit of the NF{kappa}B gene, or deleted for the iNOS gene (n=7 in each group, mean±SEM). *P<0.05 when comparing preconditioned animals with controls, #P<0.05 when comparing mice with targeted deletions to wild-types (C versus C). S, stabilization; BI, before ischemia.

 
LVEDP increased during reperfusion of wild-types, compared with pre-ischemic values and thereafter gradually decreased. The increase of LVEDP was attenuated by preconditioning (P<0.001) (Fig. 2). Mice lacking the p105 gene had less severe increase of LVEDP than wild-types (P<0.001), but no additional attenuation was afforded by preconditioning. Deletion of the iNOS gene did not influence LVEDP compared with wild-type. No beneficial effect on LVEDP was afforded by preconditioning (Fig. 2).

3.3.2. Coronary flow, heart rate, first derivatives of pressure and occurrence of arrhythmias
No significant differences could be detected between groups in these parameters.

3.3.3. Infarct size
After 1h reperfusion after global ischemia, approximately 35% of myocardial tissue was evaluated to be infarcted by TTC staining in wild-type mice. Preconditioning reduced this to about 24% (P<0.05) (Fig. 3). Infarct size in mice deleted for p105 or iNOS were not significantly different from wild types. Preconditioning did not reduce the amount of infarcted tissue in these animals (Fig. 3).



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  		Fig. 3. Infarct size after 60min reperfusion of the mouse hearts described in legend to Fig. 2. The bar graph shows the infarcted tissue in % of total left ventricular tissue after triphenyl tetrazolium chloride-staining of 1mm sections of the whole hearts, and adding together areas of all sections for further calculations (n=7 in each group, mean±SEM). *P<0.05 when comparing preconditioned animals with controls. There were no significant differences between wild-type and gene deleted animals.

 
3.3.4. Translocation of NF{kappa}B during global ischemia and reperfusion
Possible NF{kappa}B activation during Langendorff-perfusion and its modification by preconditioning was evaluated by EMSA of nuclear proteins from hearts of wild-type and p105 knockout animals. During Langendorff-perfusion before ischemia a faint band was visible after hybridizing the NF{kappa}B probe with nuclear extracts from hearts of some wild-type animals. At the end of 40min global ischemia in wild-type controls, however, NF{kappa}B was activated, and some activation was also apparent after 20min of reperfusion (Fig. 4). Limb preconditioning abolished the activation of NF{kappa}B during ischemia (Fig. 4). In cardiac nuclear protein extracts of animals with targeted deletion of the p105 gene, no bands appeared on the gels (Fig. 4).



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  		Fig. 4. A representative EMSA of cardiac nuclear protein extracts from wild-type (B6,129) or NF{kappa}B p105 knockout (p105–/–) animals with a radiolabeled NF{kappa}B probe. Hearts were harvested after 25min Langendorff-perfusion (p), at the end of 40min global ischemia (i), or after 20min of reperfusion (r) 24h after sham treatment (C) or hind limb preconditioning (LPC). When densitometry was performed on three-independent experiments, the values for B6,129 mice were LPCp, 3±0.5x104; LPCi, 1±0.5x104; LPCr, 4±0.8x104; Cp, 2±0.8x104; Ci, 6±2.5x104; Cr, 3±1.5x104 (mean±SEM).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
The main findings of the present study were that brief episodes of ischemia and reperfusion to the hind limbs protected the heart 24h later against induced global ischemia. Preconditioning of the hind limbs caused activation of NF{kappa}B in both the ischemic-reperfused hind limbs and in the heart, where increased mRNA for iNOS was detected. When preconditioning was performed in mice with targeted deletions of the NF{kappa}B p105 or the iNOS gene, no adaptation to ischemia was found, but the animals had a slight improvement of left ventricular performance during reperfusion compared with wild-types. In conjunction with induced global ischemia and reperfusion, NF{kappa}B was activated in wild-type controls, but not in preconditioned hearts. NF{kappa}B activation could not be detected in the p105 knockout animals. Delayed cardiac protection with hind limb preconditioning involves signaling via NF{kappa}B, and iNOS may be one end-effector of the protection afforded.

From the present data, a dual role of NF{kappa}B in the heart is indicated; detrimental during ischemia-reperfusion injury without adaptation, but a key factor in adaptation to ischemia by hind limb preconditioning. This dual role is in accordance with the current literature. NF{kappa}B is activated by myocardial ischemia and reperfusion [15]. Inhibition of its gene products such as leukocyte adhesion molecules, cytokines, and chemokines during reperfusion protects the heart against reperfusion injury [16–18]. More direct evidence for a detrimental role of NF{kappa}B is supplied by Morishita et al. [19], who transfected rats intracoronary with a double stranded oligonucleotide containing the NF{kappa}B cis-element before coronary artery ligation. The decoy inhibited NF{kappa}B-activation during reperfusion, and concomitantly reduced infarct size [19]. When the decoy was used for transfection and heterotopic transplantation 3 days prior to Langendorff-perfusion with Krebs-Henseleit buffer containing rat leukocytes, improved cardiac function during reperfusion was found together with reduced neutrophil adherence and tissue interleukin 8 production [20].

Signaling to NF{kappa}B such as generation of oxygen free radicals and activation of protein kinase C, p38 MAP kinase, tyrosine kinase, and MAPKAP kinase 2 are crucial for the preconditioning response in various experimental models [6,7]. A role for NF{kappa}B in ischemic preconditioning of the heart is recently suggested in both classic [8] and delayed [9] models in rats and rabbits. NF{kappa}B is activated during the preconditioning episodes, and pharmacological inhibition of NF{kappa}B abolishes the cardioprotection [8,9]. In a model of classic preconditioning in the rat, the p50 subunit of NF{kappa}B is indicated to be the important unit through pharmacological studies [8]. In the present study, animals with targeted gene deletion of the p105 precursor to p50 were employed. Adaptation to ischemia was lost in these animals, indicating that the p50 subunit of NF{kappa}B is crucial for the response. In the present study, the beneficial effects on left ventricular function may have been secondary to reduction of necrosis.

We can as yet only speculate on how ischemic adaptation of the hind limb is transmitted to protection of the heart, as very few papers have attempted to address the underlying mechanisms of remote preconditioning. It is recently shown that cross-perfusion with donor blood from a preconditioned animal could evoke a protection in the host [21], indicating that blood-borne transmission of protection is likely. One factor indicated as a trigger of remote preconditioning is adenosine, as an adenosine receptor blocker abolishes the beneficial effects. No study has previously investigated the involvement of NF{kappa}B or genes it regulates in remote preconditioning.

Nitric oxide has been suggested as both a trigger and a mediator of the preconditioning response [3]. iNOS is induced in cardiac tissue as a response to preconditioning of the heart [22], as its mRNA was in the present study after hind limb preconditioning. Mice with deletion of the iNOS gene could not be preconditioned by hind limb adaptation. This is in accordance with others' findings using pharmacological inhibition of iNOS or genetic deletion of the gene [5,12,22].

One previous paper using a model of remote, delayed preconditioning targeting the brain did not protect hearts of iNOS KO mice [23], nor did it preserve in vitro vessel reactivity in arterial rings from iNOS KO [23]. Details of why iNOS contributes to remote preconditioning in the present paper is, however, not clear. The vasorelaxing effect of nitric oxide appears not to be important, as there were no differences in coronary flow between groups. Thus, other protective effects of NO must have been important.

Myocardial protection by NF{kappa}B activation may be caused by induction of a NF{kappa}B-regulated mediator as discussed above. However, myocardial protection by NF{kappa}B activation could also be caused by a downregulation of the inflammatory response during reperfusion, as NF{kappa}B activation increases its own inhibitor I{kappa}B{alpha} [13]. In the present study, hearts of preconditioned animals had less NF{kappa}B activation during the sustained ischemia. Accordingly, in HUVECs preconditioned by hydrogen peroxide, reduced upregulation of cytokines and leukocyte adhesion molecules after subsequent stimulation with TNF-{alpha} was found [24].

What is the relation between the present study and the daily cardiac surgery scenario? A considerable limitation of this work is that the step from murine physiology to humans is large. Studies on animals with genetic deletion or overexpression are a powerful scientific tool to understand gene function, and mice are the species where genetic engineering is well established. Unfortunately, murine physiology is in some aspects different from other mammals, and the findings must be extrapolated with caution. Furthermore, we chose an isolated heart model for induced ischemia and reperfusion. The advantage of the isolated heart is excellent evaluation of heart function without having to interpreter effects of preload and afterload; the disadvantage is a denervated, non-working heart lacking blood–cell interactions.

Studying the cellular and molecular mechanisms of increased cell defense towards injury may provide us with knowledge how to exploit this pharmacologically. The vision is to obtain ‘the pill the day before surgery’. The signaling of remote preconditioning may give us information how preconditioning of one organ may influence other organs, and in theory we may obtain a ‘whole body preconditioning’. A general increase of the endogenous cell defense may reduce the deleterious effects of cardiopulmonary bypass and surgery, and thus contribute to reduced morbidity and mortality.


   Acknowledgments
 
This work has been supported by grants from the Swedish Medical Research Council (11235 and 12665), The Swedish Heart-Lung Foundation, the Foundations Fredrik o Ingrid Thuring, Tore Nilsson, Åke Wiberg, Ragnhild and Einar Lundströms Memory, and the Karolinska Institutet. Guohu Li has been supported by a grant from the Wenner-Gren Foundations.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

  1. Zeeuw S, van den Doel M, Duncker DJ, Verdouw PD. New insights into cardioprotection by ischemic preconditioning and other forms of stress. NY Acad Sci 1999;874:178-191.
  2. Tähepôld P, Valen G, Starkopf J, Karaine C, Zilmer M, Vaage J. Pretreating rats with hyperoxia attenuates ischemia-reperfusion injury of the heart. Life Sci 2001;68:1629-1640.[CrossRef][Medline]
  3. Bolli R, Dawn B, Tang X-L, Qui Y, Ping P, Xuan Y-T, Jones WK, Takano H, Guo Y, Zhang J. The nitric oxide hypothesis of delayed preconditioning. Basic Res Cardiol 1998;93:325-338.[CrossRef][Medline]
  4. Gho BC, Schoemaker RG, Van den Doel MA, Duncker DJ, Verdouw PD. Myocardial protection by ischemia in non-cardiac tissue. Circulation 1996;94:2193-2200.[Abstract/Free Full Text]
  5. Takano H, Manchikalapudi S, Tang X-L, Qiu Y, Rizvi A, Jadoon AK, Zhang Q, Bolli R. Nitric oxide synthase is the mediator of late preconditioning against myocardial infarction in conscious rabbits. Circulation 1998;98:441-449.[Abstract/Free Full Text]
  6. Das DK, Engelman RM, Maulik N. Oxygen free radical signalling in ischemic preconditioning. In: Das DK, editor. Heart in stress. New York: Annals of the New York Academy of Sciences; 1999. pp. 49-65.
  7. Cohen MV, Baines CP, Downey JM. Ischemic preconditioning: from adenosine receptor to KATP channel. Annu Rev Physiol. 62. 2000. pp. 79-109.
  8. Maulik N, Sato M, Price BD, Das DK. An essential role of NFkB in tyrosine kinase signaling of p38 MAP kinase regulation of myocardial adaptation to ischemia. Fed Eur Biol Soc Lett. 429. 1998. pp. 365-369.
  9. Xuan Y-T, Tang X-L, Banerjee S, Takano H, Li RCX, Han H, Qiu Y, Li J-J, Bolli R. Nuclear factor-kB plays an essential role in the late phase of ischemic preconditioning in conscious rabbits. Circ Res. 84. 1999. pp. 1095-1109.
  10. Heissmeyer V, Krappmann D, Wulczyn FG, Scheidereit C. NF-kB p105 is a target of IkB kinases and controls signal transduction of Bcl-3-p50 complexes. Eur Mol Biol Org J. 18. 1999. pp. 4766-4778.
  11. Shinmura K, Tang XL, Wang Y, Liu SQ, Takano H, Bhatnagar A, Bolli R. Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc Natl Acad Sci. 97. 2000. pp. 10197-10202.
  12. Guo Y, Jones WK, Xuan Y-T, Tang X-L, Bao W, Wu W-J, Han H, Laubach VE, Ping P, Yang Z, Qiu Y, Bolli R. The late phase of ischemic preconditioning is abrogated by targeted disruption of the inducible NO synthase gene. Proc Natl Acad Sci. 96. 1999. pp. 11507-11512.
  13. Tahepold P, Vaage J, Starkopf J, Valen G. Hyperoxia elicits myocardial protection through a nuclear factor {kappa}B-dependent mechanism in the rat heart. J Thorac Cardiovasc Surg. 125. 2003. pp. 650-660.
  14. Valen G, Yan ZQ, Hansson GK. Nuclear factor kappa-B and the heart. J Am Coll Cardiol. 38. 2001. pp. 307-314.
  15. Li C, Browder W, Kao RL. Early activation of transcription factor NF-kB during ischemia in perfused rat heart. Am J Physiol. 276. 1999. pp. H543-H552.
  16. Gumina RJ, Newman PJ, Kenny D, Warltier DC, Gross GJ. The leukocyte cell adhesion cascade and its role in myocardial ischemia-reperfusion injury. Basic Res Cardiol. 92. 1997. pp. 201-213.
  17. Cain BS, Harken AH, Meldrum DR. Therapeutic strategies to reduce TNF-{alpha} mediated cardiac contractile depression following ischemia and reperfusion. J Mol Cell Cardiol. 31. 1999. pp. 931-947.
  18. Ono K, Matsumori A, Furukawa Y, Igata H, Shioi T, Matsushima K, Sasayama S. Prevention of myocardial reperfusion injury in rats by an antibody against monocyte chemotactic and activating factor/monocyte chemoattractant protein-1. Lab Invest. 79. 1999. pp. 195-203.
  19. Morishita R, Sugimoto T, Aoki M, Kida I, Tomita N, Moriguchi A, Maeda K, Sawa Y, Kaneda Y, Higaki J, Ogihara T. In vivo transfection of cis element ‘decoy’ against nuclear factor-kB binding site prevents myocardial infarction. Nat Med. 3. 1997(8). pp. 894-899.
  20. Sawa Y, Morishita R, Suzuki K, Kagisaki K, Kaneda Y, Maeda K, Kadoba K, Matsuda H. A novel strategy for myocardial protection using in vivo transfection of cis element ‘decoy’ against NFkB binding site. Circulation. 96. 1997(Suppl. II). pp. II-280-II-285.
  21. Dickson EW, Reinhardt CP, Renzi FP, Becker RC, Porcaro WA, Heard SO. Ischemic preconditioning may be transferable via whole blood transfusion: preliminary evidence. J Thromb Thrombolysis. 8. 1999. pp. 123-129.
  22. Xi L, Jarrett NC, Hess ML, Kukreja RC. Essential role of inducible nitric oxide synthase in monophosphoryl lipid A-induced late cardioprotection: evidence from pharmacological inhibition and gene knock out. Circulation. 99. 1999. pp. 2157-2163.
  23. Tokuno S, Chen F, Pernow J, Jiang J, Valen G. Effects of spontaneous or induced brain ischemia on vessel reactivity: the role of inducible nitric oxide synhtase. Life Sci. 71. 2002. pp. 679-692.
  24. Zahler S, Kupatt C, Becker BF. Endothelial preconditioning by transient oxidative stress reduces inflammatory responses of cultured endothelial cells to TNF-alpha. Fed Am Soc Exp Biol J. 14. 2000. pp. 555-564.



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