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Annals of Clinical & Laboratory Science 33:208-215 (2003)
© 2003 Association of Clinical Scientists

Inducible Nitric Oxide Synthase and Heme Oxygenase-1 in Rat Heart: Direct Effect of Chronic Exposure to Hypoxia

Alfredo Grilli1, Maria Anna De Lutiis1, Antonia Patruno1, Lorenza Speranza1, Federico Gizzi1, Alfonso A. Taccardi2, Pericle Di Napoli2, Raffaele De Caterina2, Pio Conti3 and Mario Felaco1
1 Departments of Biomorphology, 2 Clinical Science and Bioimaging, and 3 Oncology and Neurosciences, Faculty of Medicine and Surgery, Università degli Studi "G. d’Annunzio," Chieti, Italy

Address correspondence to Professor Mario Felaco, Department of Biomorphology, Faculty of Medicine and Surgery, University G. d’Annunzio, via dei Vestini, Chieti 66013, Italy; tel 39 087 135 55306; fax 39 087 157 4 361; e-mail mfelaco{at}unich.it.


   Abstract
Top
 Abstract
Introduction
 Methods and Materials
 Results
 Discussion
 References
 
Hypoxia is a potent regulator of various biological process. Mammalian cells respond to hypoxia by increased expression of several genes. The aim of this study was to evaluate the effects of chronic exposure to low oxygen tension on the induction of inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) in rat heart. Male Wistar rats were assigned randomly to 4 groups: (A) control rats maintained in normoxic conditions for 7 and 14 days; (B) rats maintained in hypoxic conditions for 7 and 14 days; (C) rats maintained in normoxic conditions for 7 days and then transferred to hypoxic conditions for 7 days; and (D) rats maintained in hypoxic conditions for 7 days and then transferred to normoxic conditions for 7 days. In Group A, iNOS and HO-1 immunoreactivities were not evident; in Group B these immunoreactivities increased from day 7 to 14; in Group C the immunoreactivities decreased on day 7, compared to day 14; and in Group D, the immunoreactivities increased on day 7, compared to day 14. These findings were confirmed by Western blot analyses of the respective proteins and by rt-PCR assays of the corresponding mRNAs. The results indicate that the adaptive response to hypoxia involves up-regulation of HO-1 through iNOS activation in cardiac cells. HO-1 helps to regulate vascular tone via CO and thereby participates in an important cardiac defense mechanism.

(received 18 December 2002; accepted 3 January 2003)

Keywords: nitric oxide synthase, heme oxygenase, hypoxia, oxidative stress, rat heart, carbon monoxide


   Introduction
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 Abstract
 Introduction
Methods and Materials
 Results
 Discussion
 References
 
Low oxygen tension (hypoxia) is a potent regulator of various biological processes. Mammalian cells respond to hypoxia by increasing the expression of several genes that encode for tissue-specific and ubiquitous proteins [1]. These proteins participate in diverse biological processes including erythropoiesis [2], angiogenesis [3], and glycolysis [4], which all induce cellular adaptation to stress.

Nitric oxide (NO), as a representative endothelium-derived release factor, is deeply involved in the regulation of cardiovascular function and structure [5,6]. Nitric oxide synthases (NOS) catalyze the oxygen- and NADPH-dependent oxidation of L-arginine, leading to production of L-citrulline and nitric oxide (NO) [7]. NOS is a family of enzymes with 3 major isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS) [8]. iNOS activity has been reported in various cells, including endocardial cells, endothelial cells, and neonatal and adult cardiac cells; i-NOS expression is induced by a wide spectrum of agents [9–13].

Like NO, carbon monoxide (CO) is an intracellular signaling molecule that is involved in various biological systems that activate guanylate cyclase [14]. Heme oxygenase (HO) catalyzes the oxidative degradation of heme to biliverdin, releasing equimolar amounts of CO and iron. The two isoforms of HO are products of 2 different genes. The HO-1 isoform is inducible and ubiquitously distributed in mammalian tissue; HO-2 is a constitutively expressed isoform that predominates in the central nervous system [15]. Several reports suggest that hypoxia induces iNOS and HO-1 in cultured cells [16,17].

The aim of the present study was to elucidate the effect of chronic exposure to low O2 tension on i-NOS and HO-1 gene expression in the rat heart.


   Methods and Materials
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 Abstract
 Introduction
 Methods and Materials
Results
 Discussion
 References
 
Protocol.  Adult male Wistar rats were assigned randomly to 4 groups, as follows:

Group A. Control rats (n = 10) were maintained in normoxic conditions and sacrificed on day 7 (A7; n = 5) or day 14 (A14; n = 5);

Group B. Rats (n=10) were maintained in hypoxic conditions and sacrificed on day 7 (B7; n = 5) or day 14 (B14; n = 5).

Group C. Rats (n = 10) were maintained in normoxic conditions for 7 days. Then 5 rats were sacrificed (C7); the other 5 rats were transferred to hypoxic conditions and sacrificed on day 14 (C14).

Group D. Rats (n = 10) were maintained in hypoxic conditions for 7 days. Then 5 rats were sacrificed (D7); the other 5 rats were transferred to normoxic conditions and sacrificed on day 14 (D14).

Chronic hypoxic conditions were maintained in a chamber filled with 10% O2 (76 Torr) and normal CO2 tension. The hearts were excised after anaesthetizing the rats with phenobarbital (20 mg/kg). Cardiac sections were fixed in liquid N2 and stored at -80°C.

Immunohistochemistry.  Slides were dehydrated, rinsed in phosphate buffered saline (PBS), and blocked for 30 min at room temperature in PBS that contained 5% (v/v) normal goat serum, 0.1% (v/v) bovine serum albumin, and 0.1% (v/v) Tween 20. Slides were then incubated for 60 min at 37°C with rabbit anti-iNOS and anti-HO-1 antisera (Calbiochem, Germany), which were diluted 1:1000 in PBS. The slides were washed twice in PBS for 5 min, once in Tris-HCl buffer (pH 7.6) for 6–10 min, and then rinsed in Tris-HCl buffer. The sections were incubated for 30 min with biotinylated secondary antibody. They were washed in PBS 3 times for 5 min, incubated with avidin-biotin solution for 30 min, washed in PBS 3 times for 5 min, incubated with peroxidase substrate for 5 min, washed in tap water for 5 min, and dehydrated (Rabbit ABC Staining System, Santa Cruz Biotech, Inc., Santa Cruz, CA), as previously described [18].

Western blot analysis.  Determinations of iNOS and HO-1 proteins in heart tissue were performed by Western blotting of protein extracts. Equal amounts of protein (50 mg), quantified by spectrophotometric assay, extracted from normoxic heart and hypoxic heart, were separated by electrophoresis on 7.5% (w/v) SDS-polyacrylamide gel and transferred to nitrocellulose membranes (Bio-Rad, Hercules, CA) at 4°C using glycine-methanol buffer. The nitrocellulose membranes were then blotted in tris-buffered saline (TBS)-milk and incubated overnight with anti-iNOS primary antibody (1:1000 v/v) or anti-HO-1 primary antibody (1:1000 v/v), (Santa Cruz Biotech, Inc., Santa Cruz, CA). The nitrocellulose membranes were washed in TBS-Tween 20 (0.1%, v/v), incubated with alkaline phosphatase-conjugated secondary antibody (INALCO, Cayman, CA) for 2 hr, washed again, and developed in alkaline buffer using nitrobluetetrazolium (NBT) as substrate (Alkaline Phosphatase Conjugate Substrate Kit, Bio-Rad, Hercules, CA), as previously described [19].

Reverse transcription-polymerase chain reaction (rt-PCR).  As previously described [18–20], total RNA was extracted using 1 ml RNAzol (Cinna Biotex, Houston, TX) with 20 µg E. coli rRNA (Boehringer) as a carrier. Reverse transcription was performed in a volume of 20 µl containing 2.5 µl M-MLV reverse transcriptase (Perkin-Elmer), 1 mM dNTP, 2.5 µM random primers, and 1 U/µl RNAse inhibitor (Pharmacia) for 30 sec at 42°C. Polymerase chain reaction (PCR) amplification was performed using a Termocycler Eppendorf Mastercycler 5330 at the following annealing temperatures: 55°C for 60 sec for iNOS, or 52°C for 60 sec for HO-1. The MgCl2 concentrations used for i-NOS cDNA and HO-1 cDNA amplification were 2.0 mM, with 2 U of TAq DNA polymerase (Cabiochem). The following primer pairs were used:

5'-TCTGTGCCTTTGCTCATGAC–3' (sense), 5'-CATGGTGAACACGTTCTTGG-3' (antisense) for rat iNOS;

5'-CAGAAGGGTCAGGTGTC-3'(sense), 5'-AGTAACTCCCACCTCGT-3' (antisense) for rat HO-1.

Rt-PCR was performed with 18S mRNA internal standard.

Image processing and analysis system.  Densitometric analysis was performed by using a Leica Quantimet 500-plus (Leica Cambridge, Ltd, Cambridge, UK), and determining the change in integrated optical density (IOD) using an ISO 152-3406 transmission density standard (Eastman Kodak, Rochester, NY), as previously described [21].

Statistical analysis.  Results were expressed as mean ± SD. Statistical analyses was performed using ANOVA; p <0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Methods and Materials
 Results
Discussion
 References
 
Immunohistochemistry.  The localization of iNOS and HO-1 in rat hearts was determined by immunohistochemistry (Fig. 1Go). The response to hypoxia in Group B was clearly evident. Computerized image analysis confirmed the positive immunoreactions (brown staining). In Group A, the brown staining was not evident and image analysis showed absence of detectable protein levels. In Group B, iNOS and HO-1 immunoreactions increased from days 7 to 14 (iNOS: p = 0.001, B7 vs B14; HO-1: p = 0.013, B7 vs B14) (Table 1Go).



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  		Fig. 1. Histological sections of rat hearts (40 x). Immunohistochemical studies demonstrate iNOS and HO-1 in myocardial tissue (red-brown coloration). The figure shows (for both iNOS and HO-1) low immunoreactivity on days 7 (A7) and 14 (A14), compared to hypoxic conditions (B7, B14), where the reaction was more prominent on day 14 (B14). The effect of hypoxia was also evident in Group C, where rats were maintained in normoxic condition for 7 days (C7) and then in hypoxic conditions for another 7 days (C14). The passage from the hypoxic (D7) to normoxic (D14) state shows a decrease of both iNOS and HO-1.

 

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  		Table 1. Densitometric analyses of iNOS and HO-1 protein and mRNA expression in cardiac tissue of rats in Groups A7, A14, B7, and B14. The results are expressed in integrated optical density units; IOD, mean ± SD, n = 5)
 
Effects of chronic hypoxia were also seen in Groups C and D (Fig. 1Go, Table 2Go). In Group C, iNOS immunostaining increased from day 7 to 14 (p <0.001, C7 vs C14) and HO-1 immunostaining increased from day 7 to 14 (p = 0.001, C7 vs C14). In group D, the immunostaining decreased for both iNOS (p = 0.007, D7 vs D14) and HO-1 (p = 0.002, D7 vs D14).


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  		Table 2. Densitometric analyses of iNOS and HO-1 protein and mRNA expression in cardiac tissue of rats in Groups C7, C14, D7, and D14. The results are expressed in integrated optical density units; IOD, mean ± SD, n = 5)
 
Western blot analysis.  Western blot analysis was performed to estimate the protein levels of iNOS and HO-1 in rat hearts. In Fig. 2AGo, the Western blots showed detectable levels of iNOS and HO-1 proteins. The iNOS/ß-actin and HO-1/ß-actin ratios were increased in group B compared to Group A. In Group B the iNOS protein levels increased on day 14 vs day 7 (p = 0.009, B7 vs B14) (Table 1Go). The HO-1 protein levels also showed an increase on day vs day 7 (p = 0.012, B7 vs B14) (Table 1Go). Effects of chronic hypoxia were evident in Groups C and D (Fig. 2bGo); iNOS and HO-1 proteins were evident in both groups. In Group C, iNOS and HO-1 protein levels increased on day14 vs day 7 (iNOS: p <0.001, C7 vs C14; HO-1: p <0.001, C7 vs C14) (Table 2Go). In Group D decreases were detected on day 14 vs day 7 for both iNOS and HO-1 protein levels (iNOS: p <0.001, D7 vs D14; HO-1: p = 0.042, D7 vs D14) (Table 2Go).



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  		Fig. 2. Western blots of iNOS and HO-1 proteins. Exposure to hypoxia increased cardiac iNOS and HO-1 levels (B7, B14) vs normoxic conditions (A7, A14). Hypoxia increased the iNOS and HO-1 levels (C14, D7), while return to normoxic conditions decreased the expression of both proteins (D14).

 
rt-PCR.  To estimate mRNA levels for iNOS and HO-1 in rat hearts, rt-PCR analyses were performed (Fig. 3Go). In Group A, low levels of mRNA for iNOS and HO-1 were found. In Group B, the iNOS/18S and HO-1/18S ratios were increased compared to Group A. In Group B the iNOS mRNA and HO-1 mRNA levels were increased on day 14 vs day 7 (iNOS: p <0.001, B7 vs B14; HO-1: p = 0.008, B7 vs B14) (Table 1Go).



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  		Fig. 3. rt-PCR analysis of iNOS (3A) and HO-1 (3B) in normoxic cardiac tissue (A7, A14), compared to hypoxic tissue (B7, B14), as well as in hypoxic condition (C14) after 7 days of normoxia, compared to normoxic condition after 7 days of hypoxia. The internal standard was 18S mRNA. Expression of the iNOS and HO-1 genes was increased in hearts of the hypoxic rats.

 
Effects of chronic hypoxia were also evident in Groups C and D; iNOS mRNA and HO-1 mRNA were seen in both groups. In Group C, increases of iNOS and HO-1 mRNA were observed on day 14 vs day 7 (iNOS: p <0.001, C7 vs C14; HO-1: p = 0.01, C7 vs C14), whereas in Group D, decreases were detected on day 14 vs day 7 for both iNOS and HO-1 mRNA levels (iNOS: p = 0.002, D7 vs D14; HO-1: p <0.000, D7 vs D14) (Table 2Go).


   Discussion
Top
 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
References
 
Hearts are exposed to low oxygen tension (hypoxia) in many circumstances, including pulmonary diseases, ischemia, and high altitude. During hypoxic exposures, a decline of ATP concentration, a shift to anaerobic glycolysis, and an increase of pyruvate have been observed [23]. As a consequence of the shift to anaerobic glycolysis, new enzymes are synthesized. Increasing evidence suggests that mammalian cells may adapt their pattern of gene expression to oxygen availability [24,25].

In the present study, we report the effects of hypoxia on iNOS and HO-1 gene expression. Our findings are consistent with previous observations that NOS and HO-1 activities are related and that NO increases HO-1 activity, providing cyto-protection against oxidative stress [26].

The significance of increased HO-1 expression under hypoxic conditions in the heart is not well known. HO-1 may be induced as a protective mechanism in the heart, since it has been observed that CO relaxes coronary and aortic smooth muscles. HO-1 may improve cardiac function during hypoxic conditions by increasing coronary flow [27]. iNOS can be induced by several stimuli including endotoxin, interleukin-1ß, tumor necrosis factor-{alpha} and, in cultured cardiomyocytes, by hypoxia [28].

Many factors appear to be involved in the regulation of iNOS induction in cardiomyocytes. The NO produced by iNOS causes inhibition of contractility and also inactivates glutathione peroxidase (GPX) activity in cardiomyocytes. NO might directly produce a toxic oxygen metabolite, peroxinitrite (ONOO-), which may damage cells through the peroxidation of lipid membranes [29]. NO is a potent inducer of HO-1 gene expression through an increase of oxidative stress; experimental data suggest that induction of HO-1 gene expression by NO may be a result of glutathione depletion [30].

HO-1 gene expression has an important role in protecting cells against oxidative stress. The function of this protein is to degrade the potent prooxidant heme molecule, acting as an antioxidant, and its final product, CO, is an activator of guanylate-cyclase, which is necessary for generation of cGMP. This provides evidence that HO-1 is involved in the mechanisms of cellular protection. In particular, CO increases the generation of cGMP in the course of guanylate cyclase activation; the involvement of CO in the control of cardiovascular functions through cGMP production is supported by evidence that, under stressful conditions, HO-1 is the major contributor of CO [31] .

The results of our study suggest that NO plays an important role as a scavenger of free radicals produced during the altered metabolic conditions due to hypoxia. Our data support the theory that, during hypoxic conditions, the increased induction of iNOS provides large amounts of NO. In our study, the rats that were initially maintained in hypoxic conditions and then transferred to normoxic conditions (Group D) showed decreased induction of iNOS. Our study gave similar results for HO-1 activity under the same pO2 conditions, demonstrating that NOS and HO-1 activities are linked. Our results suggest that the adaptive response to hypoxia involves up-regulation of HO-1 and iNOS in cardiac tissue, indicating that these enzymes may help to regulate vascular tone via CO and thereby participate in a pathophysiologically important defense mechanism of the heart.

In conclusion, when the antioxidant network is working efficiently, production of normal amounts of NO provides protection against the damaging effects of free radicals. However, if there is excessive production of NO, the latter can react with super-oxide anion to produce peroxynitrites, which are dangerous for the cell integrity. Our data support this theory and constitute an important step towards other experiments in the same direction.


   References
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 Abstract
 Introduction
 Methods and Materials
 Results
 Discussion
 References
 

  1. Helfman T, Falanga V. Gene expression in low oxygen tension. Am J Med Sci 1993;306:37–41.[Medline]
  2. Semenza GL. Regulation of erythropoietin production. New insights into molecular mechanisms of oxygen homeostasis. Hematol Oncol Clin North Am 1994; 8:863–884.[Medline]
  3. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992;359:843–845.[Medline]
  4. Firth JD, Ebert BL, Pugh CW, Ratcliffe PJ. Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3' enhancer. Proc Natl Acad Sci USA 1994;91:6496–6500.[Abstract/Free Full Text]
  5. Moncada S, Higgs EA. Molecular mechanisms and therapeutic strategies related to nitric oxide. FASEB J 1995;13:1319–1330.
  6. Inagami T, Naruse M, Hoover R. Endothelium as an endocrine organ. Annu Rev Physiol 1995;57:171–189.[Medline]
  7. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43:109–142.[Medline]
  8. Forstermann U, Closs EI, Pollock JS, Nakane M, Schwarz P, Gath I, Kleinert H. Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension. 1994;23:1121–1131.[Abstract/Free Full Text]
  9. Seki T, Hagiwara H, Naruse K, Kadowaki M, Kashiwagi M, Demura H, Hirose S, Naruse M. In situ identification of messenger RNA of endothelial type nitric oxide synthase in rat cardiac myocytes. Biochem Biophys Res Commun. 1996;218:601–605.[Medline]
  10. Felaco M, Di Maio FD, De Fazio P, D’Arcangelo C, De Lutiis MA, Varvara G, Grilli A, Barbacane RC, Reale M, Conti P. Localization of the e-NOS enzyme in endothelial cells and odontoblasts of healthy human dental pulp. Life Sci 2000;68:297–306.[Medline]
  11. Di Napoli P, Antonio Taccardi A, Grilli A, Spina R, Felaco M, Barsotti A, De Caterina R. Simvastatin reduces reperfusion injury by modulating nitric oxide synthase expression: an ex vivo study in isolated working rat hearts. Cardiovasc Res 2001;51:283–293.[Abstract/Free Full Text]
  12. Tanaka K, Hassall CJ, Burnstock G. Distribution of intracardiac neurones and nerve terminals that contain a marker for nitric oxide, NADPH-diaphorase, in the guinea-pig heart. Cell Tissue Res. 1993;273:293–300.[Medline]
  13. Carmignani M, Volpe AR, Boscolo P, Qiao N, Di Gioacchino M, Grilli A, Felaco M. Catcholamine and nitric oxide systems as targets of chronic lead exposure in inducing selective functional impairment. Life Sci 2000; 68:401–415.[Medline]
  14. Zhuo M, Small SA, Kandel ER, Hawkins RD. Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus. Science 1993;260:1946–1950[Abstract/Free Full Text]
  15. Zakhary R, Gaine SP, Dinerman JL, Ruat M, Flavahan NA, Snyder SH. Heme oxygenase-2: endothelial and neuronal localization and role in endothelium-dependent relaxation. Proc Natl Acad Sci U S A. 1996;93:795–798.[Abstract/Free Full Text]
  16. Palmer LA, Semenza GL, Stoler MH, Johns RA. Hypoxia induces type II NOS gene expression in pulmonary artery endothelial cells via HIF-1. Am J Physiol 1998;274 :L212–219.
  17. Choi AM, Alam J. Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol 1996;15:9–19.[Abstract/Free Full Text]
  18. Felaco M, Grilli A, Gorbunov N, Di Napoli P, De Lutiis MA, Di Giulio C, Taccardi AA, Barsotti A, Barbacane RC, Reale M, Conti P. Endothelial NOS expression and ischemia-reperfusion in isolated working rat heart from hypoxic and hyperoxic conditions. Biochim Biophys Acta 2000;1524:203–211.[Medline]
  19. Felaco M, Grilli A, De Lutiis MA, Patruno A, Libertini N, Taccardi AA, Di Napoli P, Di Giulio C, Barbacane R, Conti P. Endothelial nitric oxide synthase (eNOS) expression and localization in healthy and diabetic rat hearts. Ann Clin Lab Sci 2001;31:179–186[Abstract/Free Full Text]
  20. Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a Ca(2+)-independent nitric oxide synthase in the myocardium. Br J Pharmacol 1992;105: 575–580.[Medline]
  21. Felaco M, Di Napoli P, Contegiacomo G, Di Muzio M, Taccardi A, Giuliani P, Grilli A, De Lutiis MA, Di Giulio C, Barsotti A. Evidence of a relationship between coronary endothelial nitric oxide synthase activity and oxigen supply. Intern Med 1998;6:27–32.
  22. Di Giulio C, Grilli A, De Lutiis MA, Di Natale F, Sabatino G, Felaco M. Does chronic hypoxia increase rat carotid body nitric oxide? Comp Biochem Physiol A Mol Integr Physiol 1998;120:243–247.[Medline]
  23. McKean TA. Calcium transport mechanisms in muskrat and rat hearts. Comp Biochem Physiol A Mol Integr Physiol 2001;130: 771–780.[Medline]
  24. Gibbs CL, Loiselle DS. Cardiac Basal Methabolism. Jpn J Physiol 2001; 51:399–426.[Medline]
  25. Mu J, Brozinick JT Jr., Valladares O, Bucan M, Birnbaum MJ. A role of AMP-activated protein kynase in contraction and hypoxia-regulated glucose transport in skeletal muscle. Mol Cell 2001; 7:1085–1094.[Medline]
  26. Motterlini R, Green CJ, Foresti R. Regulation of heme oxygenase-1 by redox signals involving nitric oxide. Antioxid Redox Signal 2002;4:615–624.[Medline]
  27. Yet SF, Tian R, Layne MD, Wang ZY, Maemura K, Solovyeva M, Ith B, Melo LG, Zhang L, Ingwall JS, Dzau VJ, Lee ME, Perrella MA. Cardiac-specific expression of heme oxygenase-1 protects against ischemia and reperfusion injury in transgenic mice. Circ Res. 2001;89:168–173.[Abstract/Free Full Text]
  28. Jung F, Palmer LA, Zhou N, Johns RA. Hypoxic regulation of inducible nitric oxide synthase via hypoxia inducible factor-1 in cardiac myocytes. Circul Res 2000;86:319–325.[Abstract/Free Full Text]
  29. Kitakaze M, Node K, Komamura K, Minamino K, Hori M & Kamada T. Evidences for nitric oxide generation in cardiomyocytes: 1st augmentation by hypoxia. J Mol Cell Cardiol 1995;27:2149–2154.[Medline]
  30. Hogg N, Singh RJ, Kalyanaraman B. The role of glutathione in the transport and catabolism of nitric oxide. FEBS Lett 1996;382:223–228.[Medline]
  31. Csonka C, Varga E, Kovacs P, Ferdinandy P, Blasig IE, Szilvassy Z, Tosaki A. Heme-oxygenase and cardiac function in ischemic/reperfused rat hearts. Free Radic Biol Med 1999;27:119–126.[Medline]



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