Integrative Physiology |
From the Division of Newborn Medicine, Department of Pediatrics (H.C., T.M., H.K., S.K.), Childrens Hospital, Harvard Medical School, and Cardiovascular Biology Laboratory, Pulmonary and Critical Care Division (C.-M.H., B.A., M.A.P.), Brigham and Womens Hospital, Harvard School of Public Health, Boston, Mass.
Correspondence to Stella Kourembanas, MD, Childrens Hospital, 300 Longwood Ave, Enders 9, Boston, MA 02115. E-mail kourembanas{at}hub.tch.harvard.edu
| Abstract |
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Key Words: vascular remodeling gene expression hypoxia
| Introduction |
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A variety of cellular stressors, such as heat shock, oxidative stress, heavy metals, and hemoproteins, induce HO-1.11 12 13 Therefore, a protective/antioxidant role has been proposed for HO-1, as well as its enzymatic product, bilirubin.14 We found that SMC HO-1 is also induced by hypoxia in vitro in a time-dependent fashion with an initial 6-fold induction of mRNA at 12 hours of exposure followed by return to baseline by 48 hours of continued hypoxic exposure. This induction is accompanied by increased HO-1 activity and cGMP concentrations in vitro.6 In the rat model of chronic hypoxia, there is a sustained induction of vasoconstrictors such as ET-115 and angiotensin II,16 and although increased production of the vasodilator nitric oxide has been reported,17 18 the net balance of these agents favors active vasoconstriction and wall remodeling. We speculated that HO-1 may be transiently induced by hypoxia in the lung, representing an endogenous adaptive response and that because of its transient nature, this response is ineffective in counteracting the actions of other mediators that are persistently induced under hypoxic conditions. We thus hypothesized that sustained induction of HO-1 in the setting of hypoxia may alter this balance and prevent or ameliorate the development of pulmonary hypertension. We report here that treatment of rats with the HO-1 inducers NiCl2 and hemin caused a sustained increased expression of HO-1 in the lung and inhibited the development of structural remodeling and pulmonary hypertension by chronic hypoxia.
| Materials and Methods |
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Northern Analysis
Total lung RNA was isolated by guanidinium isothiocyanate
extraction as previously reported,20 fractionated by
formaldehyde gel electrophoresis, and transferred onto Duralose UV
membranes (Stratagene). Fifteen micrograms of total RNA was loaded in
each lane. The filters were hybridized with HO-1 and ET-1 cDNA probes
specific for the rat HO-1 gene6 and the rat ET-1
gene.9 The mouse ß-actin gene21 was used
for normalization of RNA loading. Hybridization and washes were
performed using standard conditions.19 For quantification,
the autoradiographs were scanned using a Phosphor Imager
analyzer (Molecular Dynamics).
Western Analysis
Frozen lung tissue was homogenized in lysis buffer
(containing, in mmol/L, NaCl 150, Tris [pH 7.5] 30, and PMSF 1;
0.25 mol/L sucrose; 5 µg/mL leupeptin; and 1.9 µg/mL aprotinin),
and protein concentrations were determined with a dye-binding assay
(Bio-Rad) using BSA as standard. Fifty micrograms of total lung protein
were prepared in sample buffer and boiled at 95°C for 5 minutes.
Samples were subjected to electrophoresis in a 12% SDS
polyacrylamide gel for 1 hour at 25 mA. The gel was transferred
electrophoretically onto polyvinylidene difluoride membranes
(Millipore Corp), and Western blotting was performed using primary
rabbit polyclonal antibody against rat HO-1 (1:1000 dilution) purchased
from StressGen. For detection of signal, we used an enhanced
chemiluminescence detection kit from Amersham, and for quantification,
we used Fotolook and NIH Image Software programs.
Hemodynamic Measurements
Hemodynamic measurements were performed at the
end of the experimental period of 1 week in conscious rats.
Systolic and mean right ventricular pressure (RVP)
and mean arterial blood pressure (MAP) were continuously
recorded for 2 minutes using MacLab monitoring equipment from CB
Sciences, Inc. Results are reported in mm Hg. The position of the
catheters was confirmed after the animals were euthanized.
Morphometric Analysis
Six-micrometer lung sections were stained with
hematoxylin and eosin and examined with light microscopy. At least 5
representative pulmonary arterioles chosen from
3 different sections from each animal were independently examined by 2
of the investigators (H.C. and B.A.), who were not aware of the origin
of the lung sections. The images of the arterioles were captured and
analyzed using NIH Image software.22 Blood vessels
were identified according to the accompanying airway, and intra-acinar
vessels were chosen. Percentage medial thickness was determined by
dividing the area occupied by the medial muscular layer by the total
cross-sectional area of the arteriole. This method was used to account
for uneven medial thickness and areas that had obliquely sectioned
pulmonary arterioles.
Measurement of Circulating cGMP Concentrations
Blood specimens were collected in EDTA tubes and
centrifuged, and plasma was separated and stored at 80°C
until assayed. Amprep SAX minicolumns were used to extract cGMP from
plasma samples, and plasma cGMP concentrations were measured in a
single batch by radioimmunoassay (Amersham) as previously
described.23 The sensitivity of the assay was 0.5
fmol/tube, and the antibody cross-reacted fully with cGMP and <0.001%
with other adenosine or guanosine phosphates. Intra-assay
coefficient of variation was 5%. cGMP concentrations are expressed as
pmol/L.
Statistical Methods
The nonparametric ANOVA (Kruskal-Wallis) test and
Dunn multiple-comparisons tests were used to compare median values
among groups, respectively, and differences were considered significant
if P<0.05.
| Results |
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Prevention of Hypoxia-Induced Pulmonary
Hypertension
We measured RVP as an indicator of pulmonary artery
pressure in conscious rats. Systolic RVP in normoxic rats was
7.5±2.1 mm Hg (mean±SEM, n=5) (Figure 2A
). As expected, the hypoxic animals
developed pulmonary hypertension after 1 week of exposure to
10% oxygen. Their systolic RVP was 39.7±9.8 mm Hg
(mean±SEM, n=5), which was significantly higher than that of the
normoxic controls (P=0.0071). In contrast, the hypoxic
animals treated with NiCl2 did not develop
pulmonary hypertension after 1 week of hypoxic exposure. Their
systolic RVP was 10.5±3 mm Hg (mean±SEM, n=4), which
was not statistically different from the normoxic controls.
|
Effect of HO-1 Induction on Systemic Circulation
To determine whether the effect of HO-1 induction was
restricted to the pulmonary circulation or affected the
systemic circulation, we measured MAP in conscious rats. MAP was not
significantly affected by a 1-week exposure to hypoxia
(128.2±4.9 mm Hg in normoxia versus 131±6.1 mm Hg in
hypoxia, P>0.05, n=5 per group). Treatment with
NiCl2 in the setting of hypoxia led to a
small but significant reduction in MAP (108.6±6.6 mm Hg,
P<0.05, n=5) (Figure 2B
). Treatment of normoxic
animals with NiCl2 did not affect MAP
significantly (120.2±2.3 mm Hg, n=5).
Prevention of Pulmonary Vascular Remodeling
Increased thickness of pulmonary arterioles due to
SMC hypertrophy and hyperplasia is the structural hallmark
of pulmonary hypertension.27 As shown in Figure 3A
, pulmonary arterioles in
normoxic animals were thin, whereas after 1 week of hypoxic exposure
they developed increased medial thickness characteristic of
pulmonary hypertension (Figure 3B
). In contrast, the
hypoxic animals treated with NiCl2 (Figure 3C
) or hemin (Figure 3D
) had markedly reduced vascular
remodeling and the medial thickness of their pulmonary
arterioles was comparable with that of normoxic controls.
Quantification of these structural changes in several lung sections of
all of the animals exposed to the 3 different conditions revealed
significantly increased medial thickness of pulmonary
arterioles in hypoxic animals compared with normoxic controls (49%
versus 26%, P<0.05), but essentially unchanged from
baseline normoxic medial thickness in the hypoxic animals treated with
NiCl2 (26% versus 36%; NS) (Figure 4
).
|
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Effect of HO-1 Induction in Circulating Concentrations of
cGMP
CO is known to activate guanylyl cyclase and increase cGMP
levels in SMCs.6 cGMP in turn mediates CO-induced effects
such as vasodilation and inhibition of ET-1, PDGF-B, and E2F-1
transcription.9 10 To determine whether treatment with
HO-1 inducers leads to increased levels of biologically active CO, we
measured circulating cGMP concentrations in the animals. We found that
treatment with NiCl2 led to significantly
higher circulating cGMP concentrations compared with control animals
under normoxia (26.2 versus 8.7 pmol/mL, respectively,
P<0.05) (Figure 5
). In the
hypoxic setting, treatment with NiCl2 also
increased circulating cGMP levels, but the difference did not reach
statistical significance compared with hypoxic controls (15.5 versus
9.3 pmol/mL, respectively, P>0.05). There was no difference
in cGMP levels between normoxic and hypoxic animals (8.7 versus 9.3
pmol/mL, respectively, P>0.05).
|
| Discussion |
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The mechanism(s) by which sustained HO-1 expression prevented hypoxic pulmonary hypertension remain to be elucidated. These may include direct vasodilatory and antiproliferative effects of CO, the product of HO-1, as well as antioxidant properties of bilirubin, also released from the breakdown of heme by HO-1. It is likely that reactive oxygen species may contribute to the pathogenesis of hypoxic pulmonary hypertension and bilirubin may limit this process. Indeed, the antioxidant activity of bilirubin is significantly enhanced under low oxygen conditions (2% O2) compared with that at 20% O2.14 Alternatively, the increased local production of CO in the lung may lead to increased lung cGMP levels, which are known to mediate the vasodilator and antiproliferative effects of CO. In our in vitro studies, CO/cGMP was shown to inhibit the cell cyclespecific transcription factor E2F-1; to reduce SMC proliferation in culture10 ; and to suppress the hypoxic induction of ET-1, PDGF-B, and vascular endothelial growth factor by endothelial cells.9 32 CO interferes with cell cycle progression directly at the G1/S phase via its effect on E2F-1 transcription, as well as indirectly at the G0/G1 phase via its effect on mitogen transcription (ET-1 and PDGF-B). Similar mechanisms may limit medial SMC hyperplasia in vivo.
We found increased circulating cGMP levels in response to treatment with HO-1 inducers under normoxia, demonstrating that the increase in HO-1 protein resulted in enhanced biologic activity. A suppression of the NO pathway may explain the absence of a more dramatic increase in cGMP levels under hypoxia when HO-1 inducers were used. Indeed, endothelial cellderived NO is the molecule classically described to control cGMP content in the vasculature under basal conditions. In cases of vascular injury such as pulmonary hypertension, endothelial cellderived NO production may be reduced,33 34 leading to decreased cGMP.23 We speculate that vascular SMC-derived CO may represent a compensatory response of the vasculature during hypoxia when NO production is suppressed. NO and CO share common properties of vasodilation and have been reported to inhibit SMC growth as well as to regulate gene expression. Both were shown to inhibit the DNA-binding activity of hypoxia-inducible factor-1,32 35 a key transcription factor in the hypoxic signaling pathway. It is thus reasonable to speculate that a critical balance of NO and CO is required for the maintenance of vascular tone and vessel wall integrity under physiological as well as pathophysiological conditions of hypoxia. The unraveling of the molecular mechanisms underlying hypoxia-induced vascular changes is likely to lead to the development of novel approaches in the management of disorders characterized by abnormal pulmonary vascular tone and structure such as pulmonary hypertension.
| Acknowledgments |
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Received February 4, 2000; accepted April 20, 2000.
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Y. Yu, I. Fantozzi, C. V. Remillard, J. W. Landsberg, N. Kunichika, O. Platoshyn, D. D. Tigno, P. A. Thistlethwaite, L. J. Rubin, and J. X.-J. Yuan Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension PNAS, September 21, 2004; 101(38): 13861 - 13866. [Abstract] [Full Text] [PDF] |
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H. Matsui, T. Shimosawa, K. Itakura, X. Guanqun, K. Ando, and T. Fujita Adrenomedullin Can Protect Against Pulmonary Vascular Remodeling Induced by Hypoxia Circulation, May 11, 2004; 109(18): 2246 - 2251. [Abstract] [Full Text] [PDF] |
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S. J. Gibbons and G. Farrugia The role of carbon monoxide in the gastrointestinal tract J. Physiol., April 15, 2004; 556(2): 325 - 336. [Abstract] [Full Text] [PDF] |
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F. Zhang, J. I. Kaide, L. Yang, H. Jiang, S. Quan, R. Kemp, W. Gong, M. Balazy, N. G. Abraham, and A. Nasjletti CO modulates pulmonary vascular response to acute hypoxia: relation to endothelin Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H137 - H144. [Abstract] [Full Text] [PDF] |
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C. Taille, A. Almolki, M. Benhamed, C. Zedda, J. Megret, P. Berger, G. Leseche, E. Fadel, T. Yamaguchi, R. Marthan, et al. Heme Oxygenase Inhibits Human Airway Smooth Muscle Proliferation via a Bilirubin-dependent Modulation of ERK1/2 Phosphorylation J. Biol. Chem., July 11, 2003; 278(29): 27160 - 27168. [Abstract] [Full Text] [PDF] |
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J. S. Naik and B. R. Walker Heme oxygenase-mediated vasodilation involves vascular smooth muscle cell hyperpolarization Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H220 - H228. [Abstract] [Full Text] [PDF] |
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Y.-H. Chen, S.-F. Yet, and M. A. Perrella Role of Heme Oxygenase-1 in the Regulation of Blood Pressure and Cardiac Function Experimental Biology and Medicine, May 1, 2003; 228(5): 447 - 453. [Abstract] [Full Text] [PDF] |
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G. Li Volti, F. Seta, M. L. Schwartzman, A. Nasjletti, and N. G. Abraham Heme Oxygenase Attenuates Angiotensin II-Mediated Increase in Cyclooxygenase-2 Activity in Human Femoral Endothelial Cells Hypertension, March 1, 2003; 41(3): 715 - 719. [Abstract] [Full Text] [PDF] |
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X. Yang, K. K. K. Sheares, N. Davie, P. D. Upton, G. W. Taylor, J. Horsley, J. Wharton, and N. W. Morrell Hypoxic Induction of Cox-2 Regulates Proliferation of Human Pulmonary Artery Smooth Muscle Cells Am. J. Respir. Cell Mol. Biol., December 1, 2002; 27(6): 688 - 696. [Abstract] [Full Text] [PDF] |
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D. Morse and A. M. K. Choi Heme Oxygenase-1 . The "Emerging Molecule" Has Arrived Am. J. Respir. Cell Mol. Biol., July 1, 2002; 27(1): 8 - 16. [Abstract] [Full Text] [PDF] |
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E. Dubuis, M. Gautier, A. Melin, M. Rebocho, C. Girardin, P. Bonnet, and C. Vandier Chronic carbon monoxide enhanced IbTx-sensitive currents in rat resistance pulmonary artery smooth muscle cells Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L120 - L129. [Abstract] [Full Text] [PDF] |
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J. S. Naik and B. R. Walker Homogeneous segmental profile of carbon monoxide-mediated pulmonary vasodilation in rats Am J Physiol Lung Cell Mol Physiol, December 1, 2001; 281(6): L1436 - L1443. [Abstract] [Full Text] [PDF] |
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R. Foresti, H. Goatly, C. J. Green, and R. Motterlini Role of heme oxygenase-1 in hypoxia-reoxygenation: requirement of substrate heme to promote cardioprotection Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1976 - H1984. [Abstract] [Full Text] [PDF] |
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A. M.K. Choi Heme Oxygenase-1 Protects the Heart Circ. Res., July 20, 2001; 89(2): 105 - 107. [Full Text] [PDF] |
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E. Mazza, S. Thakkar-Varia, C. A. Tozzi, and J. A. Neubauer Expression of heme oxygenase in the oxygen-sensing regions of the rostral ventrolateral medulla J Appl Physiol, July 1, 2001; 91(1): 379 - 385. [Abstract] [Full Text] [PDF] |
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N. L. Jernigan, T. L. O'Donaughy, and B. R. Walker Correlation of HO-1 expression with onset and reversal of hypoxia-induced vasoconstrictor hyporeactivity Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H298 - H307. [Abstract] [Full Text] [PDF] |
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P. Wiesel, A. P. Patel, I. M. Carvajal, Z. Y. Wang, A. Pellacani, K. Maemura, N. DiFonzo, H. G. Rennke, M. D. Layne, S.-F. Yet, et al. Exacerbation of Chronic Renovascular Hypertension and Acute Renal Failure in Heme Oxygenase-1-Deficient Mice Circ. Res., May 25, 2001; 88(10): 1088 - 1094. [Abstract] [Full Text] [PDF] |
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T. Imai, T. Morita, T. Shindo, R. Nagai, Y. Yazaki, H. Kurihara, M. Suematsu, and S. Katayama Vascular Smooth Muscle Cell-Directed Overexpression of Heme Oxygenase-1 Elevates Blood Pressure Through Attenuation of Nitric Oxide-Induced Vasodilation in Mice Circ. Res., July 6, 2001; 89(1): 55 - 62. [Abstract] [Full Text] [PDF] |
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A. Keegan, I. Morecroft, D. Smillie, M. N. Hicks, and M. R. MacLean Contribution of the 5-HT1B Receptor to Hypoxia-Induced Pulmonary Hypertension: Converging Evidence Using 5-HT1B-Receptor Knockout Mice and the 5-HT1B/1D-Receptor Antagonist GR127935 Circ. Res., December 7, 2001; 89(12): 1231 - 1239. [Abstract] [Full Text] [PDF] |
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