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Cardiovascular Research 2005 65(1):203-210; doi:10.1016/j.cardiores.2004.09.001
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Copyright © 2004, European Society of Cardiology

Heart failure increases protein expression and enzymatic activity of heme oxygenase-1 in the lung

Chen F. Lama,b, Anthony J. Croattc, Darcy M. Richardsona, Karl A. Nathc and Zvonimir S. Katusica,b,*

aDepartments of Anesthesiology, Mayo Clinic and Foundation, Rochester, MN, USA
bClinical Pharmacology and Therapeutics, Mayo Clinic and Foundation, Rochester, MN, USA
cDivision of Nephrology, Mayo Clinic and Foundation, Rochester, MN, USA

* Corresponding author. Department of Anesthesiology, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905, USA. Tel.: +1 507 255 4288; fax: +1 507 255 7300. Email address: katusic.zvonimir{at}mayo.edu

Received 6 May 2004; revised 20 August 2004; accepted 1 September 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Objective: Heart failure (HF) cell or siderophages are pulmonary macrophages that phagonicytize erythrocytes leaked from the congested capillaries due to HF. Degradation of erythrocytes and hemoglobin increases concentrations of heme in the lung. We hypothesized that the HF-induced increase in the concentration of heme up-regulates the expression and enzymatic activity of heme oxygenase (HO)-1 in the lung.

Methods: Using the aortocaval (AC) fistula model of HF, we examined the following parameters 8–10 weeks after the creation of the fistula: morphological changes in the lung by Prussian blue iron and immunohistochemical staining, HO-1 protein expression and activity in the rat lungs, and concentrations of nitrite/nitrate (NOx–) and cyclic guanosine 3',5'-monophospate (cGMP) of the lung homogenates.

Results: Iron-stained siderophages were observed only in the lungs of rats with AC fistula. Protein level and enzyme activity of HO-1 were significantly enhanced in the lung of HF rats. NOx– concentrations of the two groups were similar, but cGMP was elevated in the lung of AC fistula rats (0.34 ± 0.06 vs. 0.89 ± 0.20 pmol/mg protein, P=0.025). Staining of serial sections of the lung tissues demonstrated induction of HO-1 co-localized to iron-stained siderophages.

Conclusions: HF causes increased pulmonary HO-1 expression and activity, which emanates largely from siderophages. Up-regulation of HO-1 may have pulmonary protective in HF.

KEYWORDS Heart failure; Siderophages; Heme, oxygenase-1; p38 MAPK; cGMP


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Heme oxygenase (HO) is the rate-limiting enzyme in the catabolism of heme to yield carbon monoxide (CO) and biliverdin [1]. In relatively low doses, CO exerts several cytoprotective effects, actions arising mainly through the stimulation of p38 mitogen-activated protein kinase (p38 MAPK) pathway [2]. CO also mediates other effects in vasculature via the activation of soluble guanylyl cyclase (sGC) [3]. HO-1 is highly inducible by a variety of toxic stimuli, including free heme [1,4]. Previous studies have shown that HO-1 protects cells against oxidative and nitrosative stress, and heme-induced toxicity [5–7].

Heart failure (HF) is a condition associated with chronically elevated pulmonary capillary pressure, vascular permeability and pulmonary edema [8]. In HF, alveolar macrophages are the major cells responsible for the degradation of extravasated hemoglobin. Degradation of hemoglobin yields iron, which is stored in hemosiderin granules, and hemosiderin-laden macrophages are traditionally named HF cells or siderophages [9]. Siderophages require 33–48 h to break down hemoglobin and remain in the lungs for up to 2 weeks [10]. Pulmonary siderophages are of considerable pathophysiologic significance and are established as a marker of HF or pulmonary hemorrhage in forensic medicine and diagnostic pathology [10,11].

The breakdown of hemoglobin engulfed by macrophages necessitates, as a proximate step, availability of HO activity. Given the relatively large amounts of such heme proteins within macrophages, augmentation in HO activity can only be met by HO-1, the readily inducible isozyme, and not HO-2, the constitutive isozyme. We thus hypothesized that HO-1 would be strongly induced within iron-laden macrophages and thereby contribute to increased HO activity in the lung of HF.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1. A rat model of volume overload heart failure
This experimental model was first described more than 20 years ago [12] and has been well characterized as an appropriate animal model of heart failure [13–17]. Aortocaval (AC) fistula was produced in rats as previously described [18]. In brief, Sprague–Dawley rats (weight 200–250 g) were anesthetized with intraperitoneal injection of methohexithal sodium (50 mg/kg). Following a midline abdominal incision, the inferior vena cava (IVC) and aorta were exposed. Vascular clamps were placed across the aorta and IVC just above the aortic bifurcation and below the origin of renal vessels. The lumbar aorta was punctured with an 18-G disposable needle at the lumbar aorta above the aortic bifurcation. The needle was gradually introduced across the aorta and penetrated the neighboring wall of IVC. The needle was then withdrawn and the entry point of needle into aorta was sealed with a drop of cyanoacrylate glue. Vascular clamps were removed and abdominal wall was closed in layers. The sham-operated rats underwent laparotomy, cross-clamping of the aorta and IVC for 30 s without puncturing, and the placement of a drop of cyanoacrylate glue at the lumbar aorta. Our studies were performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

2.2. Tissue preparations
Eight to ten weeks after the creation of the AC fistula, when decompensated HF is known to develop [15], rats were weighed and then euthanized with an injection of pentobarbital (250 mg/kg, i.p.). The right lung was rapidly removed and snap-frozen at –70 °C for further examinations. Lung sections for cyclic guanosine 3',5'-monophosphate (cGMP) measurement were pre-incubated in 10–3 M 3-isobutyl-1-methylxanthine for 30 min to inhibit the degradation of cyclic nucleotides by phosphodiesterase. The left lung was dissected and fixed in 4% paraformaldehyde for histology and immunohistochemistry examinations. Lung sections were randomly selected from sham-operated and AC fistula rats, and stained using the Prussian blue method to visualize the deposition of hemosiderin [19]. Heart was sectioned and stained with Harris' hematoxylin and eosin.

2.3. Western blot analysis
Soluble protein extracts (50 µg) were loaded into polyacrylamide gels (9–12%) and transferred onto nitrocellulose membranes. Mouse monoclonal anti-endothelial nitric oxide synthase (eNOS) (1:1000; BD Transduction Labs), anti-inducible NOS (iNOS) (1:1500; BD Transduction Labs), anti-HO-1 (1:1000; Stressgen), anti-HO-2 (1:1000; Stressgen) and anti-p38 MAPK (1:1000; Cell Signaling) antibodies were used. After washing, the membranes were incubated with 1:2000 dilution horseradish peroxidase-linked secondary antibodies for 1 h at room temperature. Bands were visualized using enhanced chemiluminescence. Since tissue proteins of AC fistula rats are significantly altered due to tissue remodeling, actin was not used for loading control [20]. Equal loading of proteins for each blot was confirmed by the Ponceau staining. Protein levels were quantified by scanning densitometry (Scion Image).

2.4. p38 MAPK activity assay
Activity of p38 MAPK was determined by the p38-induced phosphorylation of ATF-2 at Thr71 [21]. Lung soluble protein extracts were assayed according to the manufacturer's instruction (Cell Signaling Technology).

2.5. Measurement of HO enzyme activity
HO activity was measured by bilirubin generation in microsomes isolated from lung [22]. Lung tissue was homogenized in phosphate buffer (pH 7.4), sonicated on ice and centrifuged at 1000 x g for 10 min at 4 °C. The resulting supernatants were centrifuged at 100,000 x g for 60 min at 4 °C. The pellet was suspended in phosphate buffer (pH 7.0) containing 2 mM MgCl2 and designated as the microsome fraction. An aliquot of the microsomal fraction was added to the reaction mixture containing rat liver cytosol (2 mg of cytosolic protein), hemin (20 µM), glucose-6-phosphate (2 mM), glucose-6-phosphate-dehydrogenase (0.2 units) and NADPH (0.8 mM), and incubated for 2 h at 37 °C in the dark. Bilirubin formed during the incubation was extracted with chloroform. The change in optical density at 464–530 nm was measured (extinction coefficient 40 mM–1.cm–1 for bilirubin). HO activity is shown as picomoles of bilirubin formed per hour per milligram protein.

2.6. Measurement of cGMP
Radioimmunoassay kits (Amersham Pharmacia) were used to measure the cGMP concentrations in the lung tissues as previously described [23].

2.7. Measurement of NO2–/NO3– (NOx–)
NOx– concentration of the lung homogenate was measured using the automated chemiluminescence assay by a NO analyzer (Ionics-Sievers) and the Griess reaction (Cayman Chemical).

2.8. Immunohistochemical staining
Mouse monoclonal anti-HO-1 (1:50; Stressgen) and CD 11b (1:50; Serotec) antibodies were used to visualize the expression on the lung sections by the avidin–biotin method (Vector Laboratories).

2.9. Statistical analysis
Results are presented as the mean ± S.E.M. Data were compared by an unpaired t-test. Statistical significance was accepted at a level of P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1. Presence of aortocaval fistula
The patency of the AC fistula 8–10 weeks after its creation was visually confirmed at the time of sacrifice. Rats exhibited a closed fistula were excluded from further study. Compared to sham-operated rats, there was a significant increase of body weight in the rats with the AC fistula (228 ± 10 vs. 416 ± 23 g, n=7, P<0.001). Siderophages were found in all lung sections of rats with AC fistula (n=7; Fig. 1A and B), but none was found in the lung of sham-operated rats (n=5). Fig. 2 shows significant hypertrophy of the ventricular cardiomyocytes in the rats with AC fistula. Increased eNOS expression due to high blood flow [24] in aortic segments above the AC fistula also confirmed the patency of fistula (Fig. 3).


Figure 1
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  		Fig. 1 Representative Prussian blue staining lung sections showing heart failure cells or siderophages (greenish-blue) in the lung tissues of AC fistula rats under light microscopy 200 x (A) and 400 x (B). Experiments were performed in seven rats with AC fistula and five sham-operated rats (lung sections of sham-operated animals were not shown).

 

Figure 2
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  		Fig. 2 Representative sections of the right ventricle of (A) sham-and (B) AC fistula-operated rats under light microscopy 400 x . Hypertrophy of cardiomyocytes (solid arrows) was found in both ventricles of the rats with AC fistula compared with shams (dashed arrows). Histological examination was performed on five animals of each group. Data of left ventricle are not shown.

 

Figure 3
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  		Fig. 3 A representative blot of protein expression of endothelial nitric oxide synthase (eNOS) of the aorta segments above and below AC fistula. Experiments were performed on four rats in each group.

 
3.2. Protein expression
eNOS, iNOS and HO-2 expressions in the lung homogenates were similar between the two groups (data not shown). However, rats with the AC fistula had significantly higher expression of HO-1 and p38 MAPK (Fig. 4A and B). Activity of p38 MAPK, as measured by the expression of phosphorylated ATF-2, also increased in the lung homogenate of these rats, although the difference did not reach a statistical significance (Fig. 4C).


Figure 4
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  		Fig. 4 Western blot analysis of protein expression of lung tissues in sham and AC fistula rats, 8–10 weeks after operation. (A) HO-1 in the sham and AC animals. n=6–9, *P=0.002. (B) p38 MAPK in the sham and AC fistula groups. n=7–9, *P<0.001. (C) Phosphorylated ATF-2 in the sham and AC groups. n=6–8, P=0.122. Images are representative blots for all experiments. Statistic analysis (unpaired t-test) was performed by comparing the densitometry values (in relative density) of bands between the two groups. Data are shown as means ± S.E.M.

 
3.3. HO enzyme activity and cGMP measurement
HO enzymatic activity, which was assessed by the formation of bilirubin, was increased in lung microsomes prepared from rats with the AC fistula (Fig. 5A). cGMP concentration of total lung homogenate was also significantly elevated in these rats (Fig. 5B).


Figure 5
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  		Fig. 5 (A) Heme oxygenase activity measured by bilirubin formation in the microsomes isolated from the lung tissues of sham and AC fistula rats. n=6–8, *P=0.01 sham vs. AC analyzed by unpaired t-test. (B) Basal cyclic guanosine cGMP concentrations in lung homogenates of sham and AC fistula rats. *P=0.025 sham vs. AC analyzed by unpaired t-test. n=6 for each group. Data are shown as means ± S.E.M.

 
3.4. NOx– measurement
There were no differences in the lung tissue NOx– concentrations between two groups as measured by both the chemiluminescence and Griess reaction assays (Fig. 6A and B).


Figure 6
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  		Fig. 6 Concentrations of nitrite/nitrate (NOx–) in the lung homogenates of sham and AC fistula rats, as measured by the chemiluminescence (A) and Griess reaction (B) assays. Unpaired t-test shows no significant difference between the two groups.

 
3.5. Histology and immunohistochemistry examinations
Immunostaining of the serial sections of the lung co-localized the expression of HO-1 and CD 11b (a macrophage/monocyte-specific antigen) in the lung (Fig. 7A and B). Serial lung sections also revealed that expression of HO-1 localized to areas of iron deposition in the lung in rats with the AC fistula (Fig. 7C and D).


Figure 7
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  		Fig. 7 Representative serial lung sections of AC fistula rats showing positive immunostaining of CD 11b (A) and HO-1 (B). Arrowheads indicate the corresponding lung areas that expressed both CD 11b and HO-1. The other representative serial lung sections of aortocaval fistula rats showing the same lung region with positive Prussian iron staining (C) and HO-1 expression (D). Arrows indicate the intralobular pulmonary artery smooth muscle. Images are shown as 400 x under light microscopy. Experiments were performed in the randomly selected lung sections of four rats with AC fistula.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
This study provides the first description of increased expression and enzymatic activity of HO-1 in the lung of experimental animals with HF, and demonstrates that such up-regulation of HO-1 emanates overwhelmingly from pulmonary siderophages.

Rats with an AC fistula can develop HF with normal sodium balance (compensated HF) or progressive sodium retention (decompensated HF) [25]. This experimental model of HF is characterized by the hemodynamic and neurohormonal changes, which closely mimic the alterations observed clinically in patients with HF [12,15,25–27]. Previous reports indicate that cardiac hypertrophy occurs within 1 week after AC fistula operation [25], while decompensated HF develops 8–16 weeks after the creation of AC fistula, characterized by circulatory congestion, decreased cardiac function and a shift in myosin heavy chain isozyme expression [15]. Increased body weight 8 weeks after AC fistula operation thus reflects the ongoing process of fluid retention due to decompensated HF in this study. We also showed hypertrophy of cardiomyocytes in the rats with AC fistula, indicating the morphological changes in the heart of these rats. To further confirm the patency of the fistula, we assessed the expression of eNOS in the aortic segments above and below the fistula. Aortic segments above fistula (which have a higher blood flow) express higher levels of eNOS. Endothelial NOS is up-regulated in the endothelium of blood vessels exposed to increased shear stress or blood flow [24]. Changes of eNOS expression in the aorta thus support the patency of fistula in the rats with HF.

Increased pulmonary blood flow is the principal initiator of HF in this model. Progressively increased pulmonary capillary pressure secondary to increased blood flow may disrupt the integrity of the capillary endothelium [28]. The weakened capillary permits the extravasation of erythrocytes, which are subsequently engulfed and degraded by macrophages. As these macrophages degrade heme proteins and accumulate iron as hemosiderin, they are transformed into siderophages. Along with extravasation of erythrocytes, exudation of fluid across the capillary wall occurs thereby giving rise to pulmonary edema. Thus, the transformation of macrophages into siderophages and the development of pulmonary edema reflect concomitant processes occurring in HF. In this study, pulmonary siderophages were detected only in rats with AC fistula by the Prussian blue staining. Detection of pulmonary siderophages with Prussian staining is thus considered as a specific marker of HF.

Compared to sham-operated rats, lung homogenate of rats with the AC fistula expressed a significantly higher protein level of HO-1. The enzymatic activity of HO-1 in these animals, as measured by the bilirubin formation, was also significantly enhanced. We then studied the downstream signaling molecules of HO-1, cGMP and p38 MAPK, in the rat lung tissues. We found that lung tissues of rats with AC fistula contained significantly higher concentrations of cGMP. Increased pulmonary concentration of cGMP in this model likely originates from up-regulation of HO-1, as there were no changes in NOS expression and NO end-metabolites in the lung homogenates. We detected an increased expression of eNOS and its phosphorylated form in the pulmonary artery trunk of rats with an AC fistula (Lam et al., unpublished observations), which is most likely due to the increased pulmonary artery blood flow following the creation of the fistula. However, lung tissue consists of heterogenous population of cells, and vascular endothelium represents only a limited cellular fraction of the intact lung. This may thus limit our ability to detect difference in eNOS expression [29]. Therefore, lung tissues were sectioned randomly from each animal in this study in order to minimize this methodological problem. Furthermore, cGMP may also be induced by the increased production of natriuretic peptides in the lungs during HF [30,31]. However, we were able to demonstrate the increase of protein level and enzyme activity of p38 MAPK in lung of rats with AC fistula, suggesting that activity of HO-1 stimulates downstream signaling molecules. By dual staining of serial lung sections, we found that CD 11b-stained cells expressed HO-1, indicating that macrophages and monocytes contribute dominantly to the expression of HO-1 in the lung. Moreover, we confirmed that lung regions with iron staining expressed high level of HO-1.

Black et al. [29] created an aortopulmonary vascular shunt in fetal lambs with increased pulmonary blood flow. Eight weeks after delivery, the investigators studied the eNOS expression, cGMP concentration and NOx– level of the lamb lung. They reported findings consistent with the results of our study. Endothelial NOS expression and NOx– levels were not affected whereas cGMP was significantly higher in the shunted lambs. In the present study, we provide evidence that increased activity of HO-1 could be an important mechanism responsible for elevation of cGMP in lung of animals with HF.

HO-1 is involved in control of a number of important cellular functions, including cell growth, inflammation and apoptosis [32]. HO-1 derived CO activates the sGC/cGMP pathway, which in turn leads to smooth muscle relaxation, inhibition of smooth muscle proliferation and inhibition of platelet aggregation [33–36]. CO also up-regulates p38 MAPK, which is responsible for the inhibition of endothelial cell apoptosis and inhibition of inflammatory cytokines [37,38]. Bilirubin and biliverdin, other products of heme catabolism, exert potent antioxidant activity [4,39]. In cultured cells, bilirubin (10 nM) completely reverses cell death elicited by a 10,000-fold excess (100 µM) concentration of H2O2 [40]. We thus suggest that induction of HO-1 may provide beneficial effects on the remodeling and cell survival in the lung of HF patients. Recently, Mumby et al. [41] reported a significantly elevated HO-1 protein concentration in patients with acute respiratory distress syndrome. The increased HO-1 in these patients was positively correlated with the concentration of ferritin and the iron saturation of transferrin, but negatively correlated with the concentration of low molecular mass redox active iron. Therefore, HO-1 may also have an important contribution in the mobilization, signaling and regulation of iron in variety disease conditions where hemoglobin is extravasated in the lung.

Using a volume overload HF model in rats, we demonstrated an increase of HO-1 expression and enzyme activity in the lung parenchyma. Morphological analysis demonstrates that HO-1 was localized in pulmonary siderophages. Increased HO-1 enzyme activity and stimulation of downstream signaling via cGMP and p38 MAPK may play an important cytoprotective role during the development of HF.


   Acknowledgement
 
This work was supported in part by National Institutes of Health Grants HL-53524, HL-58080, HL-66958 and DK-47060, and the Mayo Foundation. The authors would like to thank Janet Beckman for assistance with preparation of this manuscript. The technical advices provided by Dr. Daying Dai (the Neuroradiology Research Laboratory, Mayo Clinic) are also gratefully acknowledged.


   Notes
 
Time for primary review 17 days


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

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