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J Thorac Cardiovasc Surg 2000;119:820-825
© 2000 The American Association for Thoracic Surgery

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

THE EARLY RESPONSE GENES C-JUN AND HSP-70 ARE INDUCED IN REGIONAL CARDIAC STUNNING IN CONSCIOUS MAMMALS

From the Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin^a and the Institut für Pharmakologie und Toxikologie,^b Universität Münster, Münster, Germany.

Supported by Innovative Medizinische Forschung (IMF) Münster, the Interdisziplinäres Zentrum für Klinische Forschung (IZKF), Münster, and the Deutsche Forschungsgemeinschaft (DFG).

Address for reprints: Andreas Meissner, MD, Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Albert-Schweitzer-Str.33, D-48149 Münster, Germany (E-mail: a.meissner{at}uni-muenster.de ).

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Objectives: A reversible contractile dysfunction without necrosis after transient myocardial ischemia has been termed stunning . The molecular mechanisms underlying this phenomenon are only now beginning to be unraveled. It is conceivable that the expression of early-response genes may play a crucial role in stunning.
Methods: The expression of HSP-70, c-jun, and GRP-94 was investigated in a chronically instrumented dog model (n = 9). The left anterior descending coronary artery was occluded temporarily for 10 minutes after the animals had fully recovered from instrumentation. The wall thickening fraction was measured in the left anterior descending coronary artery and the nonischemic ramus circumflex of the left coronary artery–perfused region. When the wall thickening fraction of the left anterior descending coronary artery had recovered to 50% of preocclusion values, tissue samples were obtained from the areas perfused by the left anterior descending coronary artery and the nonischemic ramus circumflex of the left coronary artery.
Results: The messenger RNA of HSP-70 was increased to 214% ± 26% in the area perfused by the left anterior descending artery compared with that perfused by the nonischemic ramus circumflex of the left coronary artery. There was no difference in the messenger RNA of GRP-94. The HSP-70 content was elevated to 130% ± 14% in the left anterior descending artery compared with the area perfused by the ramus circumflex of the left coronary artery, and the c-jun protein content was 70% ± 25% higher in the ischemic area compared with the control area.
Conclusions: The induction of early-response genes observed here may indicate that they play an adaptive role in myocardial stunning, even in conscious mammals.

	Introduction

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A brief coronary artery occlusion results in reversible contractile dysfunction of the dependent myocardium, which is termed stunning . ¹ Stunning may gain relevance during coronary artery bypass surgery, heart transplantation, and angina pectoris and in patients with coronary artery disease. ² The underlying mechanisms are only partially known. ³ In the present study we chose to measure the expression of heat shock protein (HSP) 70, c-jun, and glucose-related protein (GRP) 94 in myocardial stunning on the basis of prior evidence indicating their protective role in cellular function, which arose from other disease models.

After ischemia and reperfusion, some cellular proteins are damaged and misfolded. This initiates intracellular repair mechanisms, which include the induction of proteins promoting correct folding and degradation of terminally damaged proteins, which include HSP-70 and GRP-94. HSPs were first described in the Drosophila species salivary gland; an increase in these proteins is apparently a standard response to injury. HSPs, such as HSP-70, are induced in myocardial ischemia followed by reperfusion. HSPs enhance the recovery from ischemic insult and protect against subsequent ischemia. ⁴ However, data on myocardial stunning in intact animals are currently not available.

A protein closely related to the canonical HSP is GRP-94. After depletion of intracellular glucose stores, increased synthesis of GRPs is induced. ⁵ This protein is involved in protein folding, Ca²⁺ binding, nuclear signaling, and secretion. ⁶ The glucose levels are reduced in ischemia.

Moreover, altered calcium turnover is thought to occur during myocardial stunning. ^2,3 Hence we hypothesized that these biochemical changes might increase the expression of GRP-94 on the RNA level. Previous work reported that myocardial infarction can induce c-jun in addition to HSP-70 production. ^7,8 C-jun is a transactivating transcription factor. It can activate activator protein–1–responsive elements in appropriate genes, and these genes may exert a cardioprotective role. Currently, no data are available concerning the expression of c-jun in myocardial stunning under any conditions or species.

To investigate biochemical mechanisms that accompany stunning, chronically instrumented dogs were used in the present study. This approach seems to be closer to physiologic situations. Other models, such as open-chest animals or isolated organ models, have been shown to be of limited clinical relevance and even to exhibit artifactual biochemical alterations. ⁹ The aim of this study was to increase our knowledge on changes of gene expression in myocardial stunning. Clearly, new insights into protective mechanisms during myocardial ischemia may lead to new therapeutic options. It has not previously been studied whether the expression of the putative protective genes HSP-70, GRP-94, or c-jun is altered in myocardial stunning in conscious mammals.

	Methods

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Animal instrumentation and physiologic interventions
The experimental protocol was approved by the local animal welfare board. The investigation conforms with the "Guide for the Care and Use of Laboratory Animals" published by the US National Institute of Health. Mongrel dogs of either sex (weight, 20-26 kg) were used. Details of the instrumentation have been published previously. ¹⁰

After instrumentation, the dogs were trained daily to accustom them to the experimental environment and to lie quietly in a cage when connected to the data acquisition system. Experiments were performed only after complete recovery from surgery and when normal blood gas values and hemodynamic variables were obtained.

Aortic and left atrial pressures were measured by using disposable pressure transducers. Pressure, flow velocity, and wall thickening signals were processed by using a 6-channel pulsed Doppler system (Baylor College of Medicine, Houston, Tex). The left ventricular micromanometer was calibrated to the pressures measured in the aorta and left atrium. The left ventricular pressure signal was electronically differentiated (Gould Inc, Cleveland, Ohio). All signals were recorded on an 8-channel thermal writing polygraph (Gould Inc).

After measurement of baseline values, left anterior descending coronary artery (LAD) ischemia was induced for 10 minutes. Ten minutes was chosen for comparability with our previous work and to exclude any subendocardial infarction. ¹¹ During reperfusion, wall thickening fraction (WTF) was followed until 50% recovery compared with baseline values occurred. When this level of recovery was reached, the animals were anesthetized with 300 mg of propofol, 0.5 mg of fentanyl, and 15 mg of midazolam. The trachea was intubated, and the dogs’ lungs were ventilated with 100% oxygen. A parasternal thoracotomy was performed, the heart was excised, and samples of the LAD-perfused and ramus circumflex of the left coronary artery (RCx)–perfused territories were frozen in liquid nitrogen. A group of 7 sham-operated animals underwent the same procedure without induction of ischemia.

Northern blotting
A modification of the method described by Chomczynski and Sacchi ¹² was used to extract total RNA from the frozen samples taken from the LAD and RCx areas.

Probes of complementary DNA were constructed by reverse transcription–polymerase chain reaction (PCR). Probes for cardiac HSP-70 and GRP-94 proteins were generated by cross-species reverse transcription–PCR. ^4,13 The PCR products were visualized on 2% agarose gels, cut out, purified by dialysis, ¹⁴ and used as probes in Northern blots.

For Northern blotting, total RNAs (20 µg) were separated on 1% denaturing agarose gels and transferred to nylon membranes (Amersham Buchler, Braunschweig, Germany) by capillary transfer in 20x standard saline citrate (SSC). To normalize the amount of RNA bound to membranes, all blots were also hybridized for the 18S ribosomal RNA, as previously described. ¹⁴

Western blotting
Frozen cardiac myocardium from the LAD and RCx areas was homogenized in 10 mmol/L NaHCO₃ and 5% sodium dodecylsulfate. Protein concentrations were determined by using the Lowry assay. ¹⁴ One hundred micrograms of homogenate sample protein was loaded per lane. These amounts were in the linear range for each protein. After gel electrophoresis, separated proteins were electrophoretically transferred to nitrocellulose membranes (Schleicher & Schuell, Dassel, Germany), as previously described. ¹⁵

Quantitative immunoblotting for HSP-70
Nitrocellulose sheets were incubated in Tris-buffered saline solution (TBS; 10 mmol/L Tris and 154 mmol/L NaCl) for 1 hour with TBS containing 0.1% Tween-20 (TTBS) and 2% bovine serum albumin and 10 minutes with TTBS to occupy nonspecific protein-binding sites on the nitrocellulose. The antibody against HSP-70 (StressGen, Victoria, British Columbia, Canada) at 1 µg/mL dilution in TTBS was incubated with the blot for 1 hour at room temperature. The antibody recognized a band at the expected molecular mass of 70 kDa, which was quantified. After several rinses in TTBS, the nitrocellulose was incubated with iodine-125 labeled anti-mouse immunoglobulin G (ICN Biomedicals, Eschwege, Germany) diluted 1:1000 in TBS and 2% bovine serum albumin for 1 hour at room temperature. After several washes with TBS, the nitrocellulose membranes were dried, and the radioactive bands were visualized in a PhosphorImager system (Molecular Dynamics, Division of Amersham Pharmacia Biotech, Buckinghamshire, United Kingdom), as described above. No additional (supposedly unspecific) bands were noted.

Quantitative immunoblotting for c-jun
Nitrocellulose sheets were incubated in TBS and 5% nonfat dry milk overnight at 4°C to occupy nonspecific protein-binding sites on the nitrocellulose. The antibody against c-jun (Oncogene, Cambridge, Mass) at 2 µg/mL dilution in TBS and 1% nonfat dry milk was incubated with the blot for 2 hours at room temperature. The antibody recognized a band at the expected molecular mass of 39 kDa, which was quantified. After several rinses in TTBS, the nitrocellulose was incubated with iodine-125 labeled anti-mouse immunoglobulin G (ICN Biomedicals) diluted 1:500 in TBS and 1% nonfat dry milk for 1 hour at room temperature. After several washes with TBS, the nitrocellulose membranes were dried, and the radioactive bands were visualized in a PhosphorImager system, as described above. No additional (supposedly unspecific) bands were noted.

Statistics
Data shown are means ± SEM. Statistical analysis was performed by using the Student t test.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Induction of ischemia by inflation of the balloon occluders led to a rapid decrease of WTF to negative values in the LAD-perfused area, whereas WTF in the RCx-perfused area remained constant (n = 9). Compared with preocclusion values (100%), WTF decreased to –27% ± 6.6% (P = .0001). The WTF before the excision of the heart was 49.0% ± 6.0%, which was reached after 43.8 ± 6.3 minutes of reperfusion. All hemodynamic and cardiodynamic alterations are shown in Table I.

mRNA levels of HSP-70 and GRP-94
Total RNA was isolated from samples of the stunned LAD-perfused myocardium and the RCx-perfused area, which served as a control. The HSP-70 mRNA content was 214% ± 25.9% in the LAD-perfused myocardium compared with that found in the RCx-perfused area (100% = 10,150 PhosphorImager units; n = 9; P = .02; Fig 1). There was no difference in the mRNA content for GRP-94 (Fig 2). In the stunned LAD-perfused territory, the content was 109% ± 10.4% compared with that found in the RCx area (100% = 185,800 PhosphorImager units), which was not statistically significant (P = .35). There were no differences in the HSP-70 and GRP-94 mRNA content between the RCx-perfused and LAD-perfused territories in sham-operated animals. This indicates that the alterations are genuinely the result of ischemia and not caused by regional variations in the expression of the genes of interest. Because no changes of GRP-94 RNA levels were noted, no effort was put into studying the protein level, which was not expected to be subsequently altered. Moreover, no appropriate antibody was available to us.

View larger version (57K): [in this window] [in a new window]   Fig. 1. Expression of mRNA for HSP-70 in stunned canine myocardium. The LAD in chronically instrumented dogs was occluded for 10 minutes followed by reperfusion until the WTF returned to 50% of the preocclusion value. Tissue was obtained from the LAD and the RCx-perfused areas. The autoradiograph of a representative Northern blot for HSP is shown. The left lane contains RNA from the RCx-perfused area, and the right lane contains RNA from the LAD-perfused area.

View larger version (52K): [in this window] [in a new window]   Fig. 2. Expression of mRNA coding for GRP-94 in stunned canine myocardium. The LAD in chronically instrumented dogs was occluded for 10 minutes followed by reperfusion until the WTF returned to 50% of the preocclusion value. Tissue was obtained from the LAD- and the RCx-perfused areas. The autoradiograph of a representative Northern blot for GRP-94 is shown. The left lane contains RNA from the RCx-perfused area, and the right lane contains RNA from the LAD-perfused area.

View larger version (67K): [in this window] [in a new window]   Fig. 3. Protein levels of HSP-70 in stunned canine myocardium. The LAD in chronically instrumented dogs was occluded for 10 minutes followed by reperfusion until the WTF returned to 50% of the preocclusion value. Tissue was obtained from the LAD- and the RCx-perfused areas. The autoradiograph of a representative Western blot is shown. The area of interest around 70 kDa is depicted. The left lane represents the RCx-perfused area, and the right lane shows the LAD-perfused area.

View larger version (50K): [in this window] [in a new window]   Fig. 4. Protein levels of c-jun in stunned canine myocardium. The LAD in chronically instrumented dogs was occluded for 10 minutes followed by reperfusion until the WTF returned to 50% of the preocclusion value. Tissue was obtained from the LAD- and the RCx-perfused area. The autoradiograph of a representative Western blot is shown. The area of interest around 39 kDa is shown. The left lane represents the RCx-perfused area, and the right lane shows the LAD-perfused area.

	Discussion

Top Abstract Introduction Methods Results Discussion References

Awake dogs, which were used in this study, are a well-established model for the investigation of myocardial stunning. Myocardial stunning was in fact first described in dogs. ¹ Numerous studies have been published, either in awake animals or (to allow a simplified method) in anesthetized animals, with conflicting results. The biochemical and hemodynamic findings in open-chest dogs were not in agreement with those in awake dogs. ⁹ The present model therefore seems to be closer to the pathophysiologic situation in patients than that found in isolated cardiac preparations. ¹⁷ Although the contractile dysfunction in stunning is well characterized, the underlying and concomitant biochemical alterations are not completely understood.

HSP-70 is a protein with protective functions in the cell. It is a member of a group of proteins that are involved in the correct folding of proteins and appropriate interaction of proteins. ¹⁸ Since their first description in 1962 by Ritossa, ^18a there has been growing evidence that the induction of HSPs is a universal response to cellular stress or injury. In isolated perfused rabbit hearts, HSP-70 levels increased after brief ischemic episodes. ¹⁹ The trigger for the induction of HSP-70 is not the pure ischemic insult.

Reperfusion seems to enhance the activation of HSP-70. In isolated rat hearts the time course for HSP-70 activation after a 20-minute period of ischemia peaked around 120 minutes. ²⁰ Increased levels of HSP-70 may result from enhanced gene transcription or prolonged half-life of the mRNA, enhanced rates of translations, or greater protein stability. ¹⁹ Our data are consistent with an important role of enhanced gene transcription in conscious mammals.

In the heart the induction of HSP-70 through preceding ischemic episodes or heat shock was accompanied by a decrease in stunning or a reduced infarct size. In transgenic mice overexpression of HSP-70 also correlated with an improved recovery of contractile force after ischemia. ^4,21 It may be asked how the time course and the magnitude of the induction observed here compares with and extends previous findings. In isolated Langendorff-perfused rabbit hearts, an occlusion of the large marginal branch of the left circumflex artery for 5 minutes, which led to stunning, doubled the content of HSP-70 mRNA, whereas 4 cycles of ischemia and reperfusion led to a 3-fold increase in HSP-70 mRNA. This increase was noted 1 hour after the start of reperfusion. ¹⁹ In isolated perfused rat hearts, 20 minutes of ischemia induced an 80-fold increase in HSP-70 mRNA in ischemic versus control hearts. ²⁰ Here we noted only smaller increases of RNA. The different species (dog) and a more physiologic set-up (conscious animal) may explain this; however, we noted a significant increase of HSP-70 on RNA and on the protein level. Thus HSP-70 may initiate a repair mechanism in the model we used. Another heat shock–related protein that may be altered during stunning is GRP-94. Interestingly, this protein was first identified in the dog heart in 1994. ²² It was suggested to play an important role in the sarcoplasmic reticular Ca²⁺ handling, nuclear signaling, protein folding, and sorting. ²³ Unlike HSP-70, which resides in the nucleus and in cytoplasmic compartments, GRP-94 is located in the cardiac sarcoplasmic reticulum. ^13,24 GRP-94 may be induced by the accumulation of unfolded proteins in the endoplasmic reticulum. ⁶ Although an increase in GRP-94 has been observed during ischemic stress in the kidney, ⁶ currently there are no data on the expression of GRP-94 in any model of cardiac ischemia. In the present model we noted no difference in the expression of GRP-94 after the induction of stunning, although the expression of another HSP, namely HSP-70, was increased. This argues against a function of GRP-94 in myocardial stunning.

No data have previously been available concerning c-jun expression in canine hearts (under either physiologic or pathophysiologic conditions). Together with c-fos, c-jun is a component of the transcription factor AP-1, which regulates the transcription of numerous cardiac genes, including ANF. ²⁵ C-jun has been reported to be increased in the heart after infarction by using rat models but not yet in the stunned myocardium. For instance, in rats c-jun was increased in the postinfarction myocardium after ligation of the left coronary artery. ²⁶ Like HSPs, c-jun was not induced by ischemia alone but required reperfusion. ²⁷ Hypoxia has also been shown to induce c-jun in cardiac myocytes. ²⁸ Although cyanide closely mimicked the effects of hypoxia, the time course of c-jun was different. ²⁸ Therefore other factors than metabolic switching seem to be involved in the regulation of c-jun. Pretreatment of cells with protein kinase inhibitors suppressed the response. ²⁹

In the present model of stunning, c-jun was increased. Increased levels ³⁰ have been reported in dilated human cardiomyopathy, but data on stunned human myocardium have not been available yet.

In summary, the present study demonstrates for the first time that HSP-70 and c-jun are increased in regional stunning in conscious mammals. This induction underscores a protective role of these genes in cardiac stunning.

	Acknowledgments

 
We thank Christina Burhoi for technical assistance.

	References

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1. Braunwald E, Kloner RA. The stunned myocardium: prolonged, postischemic ventricular dysfunction. Circulation 1982;66:1146-9. [Abstract/Free Full Text]
   
2. Bolli R. Myocardial "stunning" in man. Circulation 1992;86:1671-91. [Free Full Text]
   
3. Vroom MB, Van Wezel HB. Myocardial stunning, hibernation and ischemic preconditioning. J Cardiothorac Vasc Anesth 1996;10:789-99. [Medline]
   
4. Marber MS, Mestril R, Chi SH, Sayen MR, Yellon DM, Dillmann WH. Overexpression of the rat inducible 70-kD heat stress protein in a transgenic mouse increases the resistance of the heart to ischemic injury. J Clin Invest 1995;95:1446-56.
   
5. Lee AS. Mammalian stress response: induction of the glucose-regulated protein family. Curr Opin Cell Biol 1992;4:267-73. [Medline]
   
6. Kuznetsov G, Bush KT, Zhang PL, Nigam SK. Perturbations in maturation of secretory proteins and their association with endoplasmic reticulum chaperones in a cell culture model for epithelial ischemia. Proc Natl Acad Sci U S A 1996;93:8584-9. [Abstract/Free Full Text]
   
7. Nadal-Ginard B, Mahdavi V. Molecular basis of cardiac performance: plasticity of the myocardium generated through protein isoform switches. J Clin Invest 1989;84:1693-700.
   
8. Chien KR, Knowlton KU, Zhu H, Chien S. Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response. FASEB J 1991;5:3037-46. [Abstract]
   
9. Triana JF, Li XY, Jamaluddin U, Thomby JI, Bolli R. Postischemic myocardial "stunning": identification of major differences between the open-chest and the conscious dog and evaluation of the oxygen radical hypothesis in the conscious dog. Circ Res 1991;69:731-47. [Abstract/Free Full Text]
   
10. Wouters PF, Van Aken H, Marcus MA, Van de Velde M, Van Herck A, Flameng W. Effects of halothane and isoflurane on collateral dependent myocardium in chronically instrumented dogs. Anesth Analg 1993;77:516-25. [Abstract/Free Full Text]
    
11. Roll N, Van de Velde M, Wouters PF, Möllhoff T, Weber TP, Van Aken HK. Thoracic epidural anesthesia improves functional recovery from myocardial stunning in conscious dogs. Anesth Analg 1996;83:935-40. [Abstract]
    
12. Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156-9. [Medline]
    
13. Sorger PK, Pelham HR. The glucose-regulated protein grp94 is related to heat shock protein hsp90. J Mol Biol 1987;194:341-4. [Medline]
    
14. Linck B, Boknik P, Eschenhagen T, Muller FU, Neumann J, Nose M, et al. Messenger RNA expression and immunological quantification of phospholamban and SR-Ca(2+)-ATPase in failing and nonfailing human hearts. Cardiovasc Res 1996;31:625-32. [Medline]
    
15. Neumann J, Herzig S, Boknik P, Apel M, Kaspareit G, Schmitz W, et al. On the cardiac contractile, biochemical and electrophysiological effects of cantharidin, a phosphatase inhibitor. J Pharmacol Exp Ther 1995;274:530-9. [Abstract/Free Full Text]
    
16. Akaishi M, Weintraub WS, Schneider RM, Klein LW, Agarwal JB, Helfant RH. Analysis of systolic bulging: mechanical characteristics of acutely ischemic myocardium in the conscious dog. Circ Res 1986;58:208-17.
    
17. Sekili S, McCay PB, Li XY, Zughaib M, Sun JZ, Tang L, et al. Direct evidence that the hydroxyl radical plays a pathogenetic role in myocardial "stunning" in the conscious dog and demonstration that stunning can be markedly attenuated without subsequent adverse effects. Circ Res 1993;73:705-23. [Abstract/Free Full Text]
    
18. Beckmann RP, Lovett M, Welch WJ. Examining the function and regulation of hsp 70 in cells subjected to metabolic stress. J Cell Biol 1992;117:1137-50. [Abstract/Free Full Text]
    
18. Ritossa F. A new puffin pattern induced by heat shock and DNP in Drosophilia. Experentia. 1962;18:571-5.
    
19. Knowlton AA, Brecher P, Apstein CS. Rapid expression of heat shock protein in the rabbit after brief cardiac ischemia. J Clin Invest 1991;87:139-47.
    
20. Nishizawa J, Nakai A, Higashi T, Tanabe M, Nomoto S, Matsuda K, et al. Reperfusion causes significant activation of heat shock transcription factor 1 in ischemic rat heart. Circulation 1996;94:2185-92. [Abstract/Free Full Text]
    
21. Plumier JC, Ross BM, Currie RW, Angelidis CE, Kazlaris H, Kollias G, et al. Transgenic mice expressing the human heat shock protein 70 have improved post-ischemic myocardial recovery. J Clin Invest 1995;95:1854-60.
    
22. Cala SE, Jones LR. GRP94 resides within cardiac sarcoplasmic reticulum vesicles and is phosphorylated by casein kinase II. J Biol Chem 1994;269:5926-31. [Abstract/Free Full Text]
    
23. Little E, Lee AS. Generation of a mammalian cell line deficient in glucose-regulated protein stress induction through targeted ribozyme driven by a stress-inducible promoter. J Biol Chem 1995;270:9526-34. [Abstract/Free Full Text]
    
24. Welch WJ, Garrels JI, Thomas GP, Lin JJ, Feramisco JR. Biochemical characterization of the mammalian stress proteins and identification of two stress proteins as glucose- and Ca2+-ionophore-regulated proteins. J Biol Chem 1983;258:7102-11. [Abstract/Free Full Text]
    
25. Wei P, Inamdar N, Vedeckis WV. Transrepression of c-jun gene expression by the glucocorticoid receptor requires both AP-1 sites in the c-jun promoter. Mol Endocrinol 1998;12:1322-33. [Abstract/Free Full Text]
    
26. Reiss K, Capasso JM, Huang HE, Meggs LG, Li P, Anversa P. ANG II receptors, c-myc, and c-jun in myocytes after myocardial infarction and ventricular failure. Am J Physiol 1993;264:H760-9. [Abstract/Free Full Text]
    
27. Brand T, Sharma HS, Fleischmann KE, Duncker DJ, McFalls EO, Verdouw PD, et al. Proto-oncogene expression in porcine myocardium subjected to ischemia and reperfusion. Circ Res 1992;71:1351-60. [Abstract/Free Full Text]
    
28. Webster KA, Discher DJ, Bishopric NH. Regulation of fos and jun immediate-early genes by redox or metabolic stress in cardiac myocytes. Circ Res 1994;74:679-86. [Abstract/Free Full Text]
    
29. Webster KA, Discher DJ, Bishopric NH. Induction and nuclear accumulation of fos and jun proto-oncogenes in hypoxic cardiac myocytes. J Biol Chem 1993;268:16852-8. [Abstract/Free Full Text]
    
30. Wu XS, Fowler MB, Gullestad L, Webster KA, Bishopric NH. Induction of c-jun in human dilated cardiomyopathy. Circulation 1997;96(Suppl):I446.
    

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