1 Pediatric Heart Lung Center, Department of Pediatrics, and 2 Cardiovascular Pulmonary Research Laboratory, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262
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ABSTRACT |
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Nitric oxide (NO) is a potent vasodilator and inhibitor of vascular remodeling. Reduced NO production has been implicated in the pathophysiology of pulmonary hypertension, with endothelial NO synthase (NOS) knockout mice showing an increased risk for pulmonary hypertension. Because molecular oxygen (O2) is an essential substrate for NO synthesis by the NOSs and biochemical studies using purified NOS isoforms have estimated the Michaelis-Menten constant values for O2 to be in the physiological range, it has been suggested that O2 substrate limitation may limit NO production in various pathophysiological conditions including hypoxia. This review summarizes numerous studies of the effects of acute and chronic hypoxia on NO production in the lungs of humans and animals as well as in cultured vascular cells. In addition, the effects of hypoxia on NOS expression and posttranslational regulation of NOS activity by other proteins are also discussed. Most studies found that hypoxia limits NO synthesis even when NOS expression is increased.
acute hypoxia; chronic hypoxia; pulmonary hypertension; nitric oxide synthase; isolated perfused lung
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INTRODUCTION |
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NITRIC OXIDE (NO) is a potent systemic and pulmonary vasodilator that also inhibits smooth muscle cell proliferation (10, 18, 57), migration (4, 56) and inflammation and matrix protein production (40, 68). Hence reductions in NO production in the lung may contribute to the development of pulmonary hypertension by both increasing vascular tone and promoting vascular remodeling. Studies in transgenic mice show that deletion of the endothelial NO synthase (eNOS) gene leads to development of pulmonary hypertension, which is reversed by inhalation of NO (14, 64, 65). Because chronic inhaled NO also attenuates hypoxia-induced pulmonary hypertension in rats (34, 53, 55), numerous studies have examined whether reduced NO production by the lung contributes to the pathogenesis of hypoxia-induced pulmonary hypertension.
Two main sites of NO production have been described in the lung, the vasculature, and the airways (21, 22, 33, 63). NO production in the vascular endothelium is catalyzed by eNOS (type III NOS), although some studies have suggested that the other two isoforms of NOS, inducible NOS (iNOS or type II NOS) and neuronal NOS (nNOS or type I NOS), may also be present in the vasculature and contribute to NO production (48, 49). In the airways, all three isoforms have been detected in bronchial epithelium (33, 60). Whether NO produced in the airways affects pulmonary vascular tone and the development of pulmonary hypertension is unclear.
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OXYGEN SENSITIVITY OF NOS ISOFORMS |
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Molecular oxygen (O2) is an essential substrate for NO synthesis by NOS, and biochemical studies using purified NOS isoforms have estimated the Michaelis-Menten constant (Km) values for O2 to be in the 5-20 µM range (50, 51) and for nNOS to be as high as 400 µM (2). Several studies (1-3, 27) have shown that when NO is formed, it can bind to the heme iron of NOS, which inhibits NOS activity and increases the apparent Km for O2. Because O2 and NO compete for the heme iron of nNOS, the overall O2 dependence of this isoform depends on the rate of decay of the heme iron-NO complex, which is itself dependent on O2 concentration (2). Because the apparent O2 sensitivities of the NOS isoforms are within the range of tissue O2 concentrations, Rengasamy and Johns (51) have suggested that O2 substrate limitation may regulate NO production in pathophysiological conditions including hypoxia. However, whether these in vitro data could be extrapolated to NO production in the hypoxic lung was uncertain, and numerous investigators have examined the effects of hypoxia on NO production in human subjects, intact animals, perfused lungs, and cultured cells. This review compares these various studies of the acute and chronic effects of hypoxia on NO production in the lung as well as in cultured cells.
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GUANOSINE 3',5'-CYCLIC MONOPHOSPHATE AS AN INDEX OF NO SYNTHESIS |
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Because NO stimulates soluble guanylyl cyclase (sGC) and
hence cGMP formation, a number of studies (30, 54, 61, 62) have measured cGMP levels in isolated vessels and cultured cells exposed to hypoxia to assess the effects of hypoxia on NO production. For the most part, these studies showed reduced cGMP levels with exposure to hypoxia, suggesting that NO production is decreased by low
O2 tension. However, cGMP levels may not necessarily
directly reflect changes in NO production. Steady-state cGMP levels are determined by the rate of cGMP breakdown by phosphodiesterases and the
rate of cGMP formation by sGC, and although in many of the studies,
breakdown of cGMP was blocked with phosphodiesterase inhibitors,
NO-independent changes in sGC activity with hypoxia were generally not
accounted for. It is now clear that other vascular products can
regulate cGMP formation; for example, superoxide anion-derived hydrogen
peroxide is an important O2-sensitive regulator of vascular
cGMP formation (for a review, see Ref. 71). In addition, recent studies in rats suggested that chronic hypoxia increases lung
sGC expression and activity (36) and that increased cGMP production by hypoxia-induced hypertensive lungs is due to atrial natriuretic peptide rather than NO (41). Many of the
studies examining the effects of hypoxia on NO-stimulated cGMP
formation were performed before the development of sensitive
instruments for directly measuring NO and its immediate products
(nitrite, peroxynitrite, and nitrate; NO
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ACUTE HYPOXIA AND NO PRODUCTION IN ANIMAL MODELS |
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Several studies have addressed the effects of acute
ventilation with hypoxic gas on NO production in isolated
perfused lungs (Table 1).
Perfusate NO
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Several studies of perfused rabbit lungs have found somewhat different
effects of acute hypoxia on perfusate NO
Only one study has examined the relative importance of vascular versus
airway hypoxia. Ide et al. (28) examined the effects of
perfusate hypoxia alone, alveolar hypoxia alone, and combined perfusate
and alveolar hypoxia using a membrane oxygenator-deoxygenator on the
inlet limb to the pulmonary artery in perfused rabbit lungs to control
perfusate PO2 separate from alveolar
PO2. The authors found that perfusate hypoxia
alone did not affect either perfusate NO
From these studies, it seems that although acute hypoxia reduces NO
production in both piglet and rabbit lungs, the severity of hypoxia
required to do so differs. Although 7.5% O2 reduced exhaled NO production in piglet lungs (43), 6%
O2 did not reduce exhaled NO in rabbit lungs, but
3%
O2 did (7, 20, 28). Similarly, moderate
hypoxia (7.5% O2) reduced perfusate NO
1% O2 (7, 28,
32). Whether the more severe level of hypoxia that is apparently
required to reduce NO production in rabbit lungs compared with piglet
lungs is due to a species or age difference is unclear.
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ACUTE HYPOXIA AND NO PRODUCTION IN HUMANS |
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Several studies in normal humans (Table
2) have examined the effects of acute
hypoxia on exhaled NO production. Although measurements of exhaled NO
in subjects wearing a noseclip can include NO produced by both the lung
and the nasopharynx, measurements made during endotracheal intubation
should exclude the nasopharynx and just represent NO produced by the
lung. Tsujino et al. (69) measured exhaled NO using both
approaches. The concentration of exhaled NO was ~55-60% lower
with intubation than with the noseclip, suggesting that in normal
humans only ~40-45% of NO in exhaled air originates from the
lungs, with the remainder originating from the nasopharynx. In the
subjects wearing a noseclip, inhalation of hypoxic gas (10%
O2) for 3 min did not affect exhaled NO (69). Schmetterer et al. (59) examined the effects of breathing
10-100% O2 on exhaled NO measured from end-expiratory
single-breath exhalation with nasal occlusion. They observed
concentration-dependent changes in exhaled NO during graded
O2 breathing; exhaled NO levels were 31 ± 3 parts/billion while breathing room air and increased by 25% with 100%
O2. Although exhaled NO levels while breathing 10% O2 were 26 ± 3 parts/billion, this was not
significantly less than baseline (59). Dweik et al.
(13) measured real-time bronchiolar NO levels in normal
individuals by sampling gas through a bronchoscope and found that
exhaled NO levels were reduced with hypoxia (5-15% O2). Small decreases in NO levels were seen between 21 and
10%, but exhaled NO decreased by 60% in subjects breathing 5%
O2. Dweik et al. calculated the apparent
Km for O2 to be 190 µM, which is well within the physiological range (0-250 µM). None of these studies measured the effects of hypoxia on plasma
NO
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NO PRODUCTION IN CULTURED CELLS EXPOSED TO HYPOXIA |
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Several studies have examined the regulation of NOS activity by
O2 tension in cultured cells (Table
3). Hong et al. (26) measured NO production in cultured smooth muscle cells under basal conditions and after induction of iNOS (type II NOS) with bacterial lipopolysaccharide and interferon-. Although 0.2% O2
did not suppress NO production under basal conditions, it did reduce NO production when iNOS expression was induced. Cormick et al.
(9) found that although hypoxia increased iNOS gene
expression in macrophages activated with lipopolysaccharide and/or
interferon-
, NO synthesis was markedly reduced. By exposing cells to
a range of O2 tensions, Cormick et al. estimated the
Km for iNOS to be around 11% O2,
which is considerably higher than the O2 tension in tissues
and similar to that reported for purified recombinant iNOS
(9). Hence, although hypoxia may increase iNOS expression in cultured cells, it also limits NO production by the enzyme.
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Whorton et al. (70) examined the effects of graded hypoxia on thapsigargin-stimulated NO production by eNOS (type III NOS) in bovine aortic endothelial cells (BAECs). Exposure to hypoxia caused a concentration-dependent reduction in NO production as the severity of hypoxia was increased. Thus Whorton et al. suggested that O2 may be an important determinant of eNOS activity and NO production in hypoxic tissues and vascular beds such as the pulmonary arterial and fetal circulations where PO2 can be low. Xu et al. (72) also exposed cultured BAECs to hypoxia and found that NO production by eNOS stimulated with the calcium ionophore A-23187 was reduced compared with NO production by normoxic cells stimulated with the same agent. These authors also reported that cyclooxygenase inhibition prevented the hypoxia-induced decrease in NO production and that iloprost, a prostacyclin analog, directly suppressed NO production. They suggested that endothelium-derived prostanoids produced in response to hypoxia rather than reduced O2 itself regulated NO production via an autocrine negative-feedback mechanism.
In addition to the effects of hypoxia on the availability of O2 substrate for NO synthesis, a recent study by Su and Block (66) showed that hypoxia may also affect NOS activity by reducing 90-kDa heat shock protein (HSP90) levels. HSP90 has been shown to bind to eNOS and to increase its activity in response to agonists that stimulate production of NO (17). Su and Block found that hypoxia reduced eNOS activity but not eNOS protein levels in pulmonary arterial endothelial cells (PAECs) and showed that the reductions in eNOS activity were due to a decrease in HSP90 levels caused by calpain. Whether HSP90 and calpain regulate eNOS activity in the hypoxic lung in vivo remains to be determined.
A number of studies have shown that O2 tension affects eNOS gene expression in cultured cells. Liao et al. (35) found that exposure to 24 h of 3% O2 reduced eNOS mRNA and protein levels in bovine PAECs compared with cells cultured in 20% O2. Similarly, hypoxic exposure reduced both eNOS gene transcription and mRNA stability after 24-48 h in human umbilical vein endothelial cells (HUVECs) (39). In cocultures with smooth muscle cells, the hypoxic HUVECs also stimulated less cGMP formation than corresponding normoxic cells. North et al. (44) reported that as O2 tension was increased from 50 to 150 mmHg, eNOS mRNA, protein, and activity increased in ovine fetal PAECs. Hence these studies indicated that NO production by eNOS may be reduced in hypoxia through transcriptional and posttranscriptional regulation of eNOS expression as well as through reductions in eNOS activity due to reduced O2 substrate.
In contrast to these reports of hypoxic inhibition of NO synthesis and NOS expression, Hampl et al. (23) found that acute hypoxia increased basal and bradykinin-stimulated NO production in cultured bovine PAECs. The increase in NO production was attributed to hypoxia-induced increases in cytosolic calcium. Arnet et al. (6) reported that although hypoxic exposure increased eNOS mRNA and protein expression in BAECs, eNOS activity was unaffected. Whether HSP90 limited eNOS activity in the hypoxic BAECs was not determined. Justice et al. (31) compared cultured endothelial cells from resistance and nonresistance epicardial arteries and found that although hypoxia increased NO production and eNOS protein in both cell populations, eNOS mRNA increased only in the nonresistance epicardial endothelial cells, suggesting that increased NO production in the microvascular (resistance) endothelial cells may be due to translational or posttranslational regulation.
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NO PRODUCTION IN THE CHRONICALLY HYPOXIC LUNG |
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Numerous studies have measured lung NO production in animal models
of chronic hypoxia-induced pulmonary hypertension (Table 4). Fike et al. (16)
exposed neonatal pigs to hypoxia (10% O2) for 10-12
days. Plasma NO
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Three studies (29, 42, 58) have examined NO production in
perfused lungs from chronically hypoxic rats. All three studies found
perfusate NO
Exhaled NO production has been shown to be reduced in humans with chronic obstructive pulmonary disease, and a recent report by Clini et al. (8) reported that NO production from the airways was lower and inversely related to the development of cor pulmonale in patients with severe chronic obstructive pulmonary disease. It is unknown whether these reductions in exhaled NO in patients with cor pulmonale are due to hypoxia or other mechanisms.
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CONCLUSIONS AND UNANSWERED QUESTIONS |
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Although perfused lung studies show that acute moderate to severe
hypoxia can reduce exhaled NO and perfusate NO
Whether reduced NO production contributes to hypoxic pulmonary vasoconstriction is controversial. Some studies using pulmonary artery rings have reported that blockade of NOS activity inhibits hypoxic vasoconstriction (19, 67), whereas other ring studies and all perfused lungs studies have shown that inhibition of NO production potentiates hypoxic vasoconstriction (5, 25, 38). Interestingly, Hasunuma et al. (25) also reported that acute inhibition of NO synthesis had little effect on baseline pulmonary vascular resistance in either perfused rat lungs or intact rats, suggesting that basal NO production is not solely responsible for the low vascular tone of the normoxic rat lung. Although the role of NO in hypoxic pulmonary vasoconstriction is unclear, studies have shown that endogenous NO production actively opposes vasoconstrictor stimuli in the lungs of rats with chronic hypoxia-induced pulmonary hypertension (29, 45). So although inhibition of NO production may not be the sole factor responsible for the development of hypoxia-induced pulmonary hypertension, NO synthesis in the hypoxic lung may play an important role in attenuating the severity of the disease. The vast majority of studies reviewed above suggest that reduced O2 tension may limit NO production by NOS despite increases in lung NOS expression observed in some species. Most studies implicate reduced O2 substrate as the limiting factor, but the role of other factors such as HSP90 in the regulation of NO production in the hypoxic lung remains to be defined.
Recently, the role of NO in attenuating hypertensive pulmonary vascular remodeling has been questioned in a study by Quinlan et al. (47). These investigators found that in contrast to other studies (14, 64), their eNOS-deficient mice showed decreased muscularization and wall thickening of small pulmonary arteries in response to chronic hypoxia. The authors suggested that differences in the genetic background of the eNOS-deficient and control mice might have accounted for the opposite findings in their study versus those of Fagan et al. (14) and Steudel et al. (64). The role of NO in the pathogenesis of chronic pulmonary hypertension is still controversial and has recently been reviewed by Hampl and Herget (24). There is evidence for both increased and reduced NO production in chronic pulmonary hypertension, and Hampl and Herget present evidence for both beneficial and potentially adverse effects of increased NO in the development of this disease. They suggest that the protective and adverse effects of NO in pulmonary hypertension are determined by the relative amounts of NO and reactive oxygen species and that the balance may be shifted toward injury during exacerbations of chronic diseases associated with pulmonary hypertension (24).
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NOTE ADDED IN PROOF |
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Since acceptance, two additional papers that are relevant to this review have been published. Otto and Baumgardner have described hypoxic inhibition of NO production by cultured macrophages. (Otto CM and Baumgardner JE. Effect of culture PO2 on macrophage (RAW 264.7) nitric oxide production. Am J Physiol Cell Physiol 280: C280-C287, 2001). Budts et al. showed that iNOS gene transfer reduced hypoxia-induced pulmonary hypertension and vascular remodeling in mice (Budts W, Pokreisz P, Nong Z, Van Pelt N, Gillijns H, Gerard R, Lyons R, Collen D, Bloch KD, and Janssens S. Aerosol gene transfer with inducible nitric oxide synthase reduces hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats. Circulation 102: 2880-2885, 2000).
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ACKNOWLEDGEMENTS |
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We thank Drs. B. Fouty and J. Weil for critical review of the manuscript.
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FOOTNOTES |
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This work was supported by an American Heart Association Scientist Development Award (to T. D. Le Cras) and National Heart, Lung, and Blood Institute Grant HL-14985 (to I. F. McMurtry).
Address for reprint requests and other correspondence: T. D. Le Cras, Dept. of Pediatrics, Box C218, Univ. of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262 (E-mail: Timothy.Lecras{at}uchsc.edu).
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