Oxidative and nitrosative stress in pediatric pulmonary hypertension: Roles of endothelin-1 and nitric oxide

doi:10.1016/j.vph.2006.08.005

Vascular Pharmacology

Volume 45, Issue 5, November 2006, Pages 308-316

https://doi.org/10.1016/j.vph.2006.08.005 Get rights and content

Abstract

An increasing number of studies implicate oxidative stress in the development of endothelial dysfunction and the pathogenesis of cardiovascular disease. Further, this oxidative stress has been shown to be associated with alterations in both the endothelin-1 (ET-1) and nitric oxide (NO) signaling pathways such that bioavailable NO is decreased and ET-1 signaling is potentiated. However, recent data, from our groups and others, have shown that oxidative stress, ET-1, and NO are co-regulated in a complex fashion that appears to be dependent on the cellular levels of each species. Thus, when ROS levels are transiently elevated, NO signaling is potentiated through transcriptional, post-transcriptional, and post-translational mechanisms. However, in pediatric pulmonary hypertensive disorders, when reactive oxygen species (ROS) increases are sustained by ET-1 mediated activation of smooth muscle cell ET_A subtype receptors, NOS gene expression and NO signaling are reduced. Further, increases in oxidative stress can stimulate both the expression of the ET-1 gene and the secretion of the ET-1 peptide. Finally, the addition of exogenous NO, and increasingly utilized therapy for pulmonary hypertension, can also lead to increases ROS generation via the activation of ROS generating enzymes and through the induction of mitochondrial dysfunction. Thus, this manuscript will review the available data regarding the interaction of oxidative and nitrosative stress, endothelial dysfunction, and its role in the pathophysiology of pediatric pulmonary hypertension. In addition, we will suggest avenues of both basic and clinical research that will be important to develop novel pulmonary hypertension treatment and prevention strategies, and resolve some of the remaining clinical issues regarding the use of NO augmentation.

Section snippets

Endothelin-1 and nitric oxide: key regulators of pulmonary vascular resistance

ET-1, a 21 amino acid polypeptide produced by vascular endothelial cells, has potent vasoactive properties (Yanagisawa et al., 1988). The gene for human ET-1 is located on chromosome 6 and is translated to a 203-amino acid peptide precursor (preproET-1), which is then cleaved to form proendothelin-1. Proendothelin, big ET-1, is then cleaved by a membrane bound metalloprotein converting enzyme (Endothelin Converting Enzyme-1, ECE-1) into its functional form. ECE-1 exists in two isoforms, ECE-1α

Endothelin-1 and oxidative stress

An increasing number of studies implicate oxidative stress in the pathogenesis of cardiovascular disease and the development of endothelial dysfunction (Katusic, 1996, Cai and Harrison, 2000). Many ROS possess unpaired electrons and are thus free radicals. These include the superoxide anion, the hydroxyl radical, NO, and certain oxidized lipids. Other ROS such as hydrogen peroxide, peroxynitrite, and hypochorous acid, are not free radicals but are oxidizing molecules that can contribute to the

Interplay between oxidative and nitrosative stress

An emerging concept in signal transduction is that ROS can act as intracellular messengers (Griendling et al., 2000). While the modality of signal transduction by ROS is far from completely understood, it is believed that ROS are necessary components in transducing the mitogenic effects of a number of growth factors. Indeed, it is now becoming apparent that H₂O₂ has an increasingly important and variable role in mammalian cell physiology. Under normal physiological conditions, most

Pediatric pulmonary hypertension and endothelial dysfunction

Pulmonary hypertensive disorders are a significant source of morbidity and mortality in the pediatric population. In neonates, the most common etiology results from a failure to undergo the normal fall in pulmonary vascular resistance at birth (persistent pulmonary hypertension of the newborn, PPHN), with an incidence of ∼ 1 per 1000 live births. However, other pulmonary abnormalities, such as congenital diaphragmatic hernia, respiratory distress syndrome, and bronchopulmonary dysplasia, may

Nitric oxide-cGMP augmentation

NO donor compounds (i.e. nitroglycerin and sodium nitroprusside) have had a major role in the treatment of vascular disorders for decades. Following the more recent discoveries of NO biology, the use of free inhalation NO gas has emerged as an important treatment for a variety of pulmonary vascular and parenchymal diseases. Currently, its major use is as a selective pulmonary vasodilator, secondary to rapid inactivation by hemoglobin, in newborns with persistent pulmonary hypertension, and

Summary and future directions

As detailed above previous studies have implicated the oxidative stress mediated by O₂^·− and H₂O₂ in the pathophysiology of a number of cardiovascular disorders. Furthermore, we have previously shown that antioxidants attenuate FPASMC growth and at high doses induce apoptosis in vitro (Wedgwood and Black, 2003a) and increase NO-signaling in vivo (Brennan et al., 2003a, Wedgwood et al., 2005), suggesting that antioxidant therapy may represent a useful treatment strategy for patients with

Acknowledgments

This research was supported in part by grants HL60190 (to SMB), HL67841 (to SMB), HL72123 (to SMB), HL70061 (to SMB), and HL61284 (JRF) from the National Institutes of Health, and 0330292Z from the American Heart Association Pacific Mountain Affiliates (to SMB).

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Pulmonary arterial hypertension (PH) is a fatal disease marked by excessive pulmonary vascular cell proliferation. Patients with idiopathic PH express endothelin-1 (ET-1) at high levels in their lungs. As the activation of both types of ET-1 receptor (ETA and ETB) leads to increased generation of superoxide and hydrogen peroxide, this may contribute to the severe oxidative stress found in PH patients. As a number of pathways may induce oxidative stress, the particular role of ET-1 remains unclear. The aim of this study was to determine whether inhibition of ET-1 signaling could reduce pulmonary oxidative stress and attenuate the progression of disease in rats with occlusive-angioproliferative PH induced by a single dose of SU5416 (200 mg/kg) and subsequent exposure to hypoxia for 21 days. Using this regimen, animals developed severe PH as evidenced by a progressive increase in right-ventricle (RV) peak systolic pressure (RVPSP), severe RV hypertrophy, and pulmonary endothelial and smooth muscle cell proliferation, resulting in plexiform vasculopathy. PH rats also had increased oxidative stress, correlating with endothelial nitric oxide synthase uncoupling and NADPH oxidase activation, leading to enhanced protein nitration and increases in markers of vascular remodeling. Treatment with the combined ET receptor antagonist bosentan (250 mg/kg/day; day 10 to 21) prevented further increase in RVPSP and RV hypertrophy, decreased ETA/ETB protein levels, reduced oxidative stress and protein nitration, and resulted in marked attenuation of pulmonary vascular cell proliferation. We conclude that inhibition of ET-1 signaling significantly attenuates the oxidative and nitrosative stress associated with PH and prevents its progression.
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Stimulation of ET-1 receptors at the plasma or nuclear membrane induces Ca2+ release, NO, and reactive oxygen species formation in the cytosol or nucleus (5, 30). Cardiovascular disease pathogenesis involves oxidative stress and further alteration of ET-1 and NO signaling pathways (30, 31). ET-1 immunoreactivity is expressed within the cytoplasm on the membranes of the endoplasmic reticulum (ER), mitochondria, and cytosolic vesicles of endothelial cells from human (4) and various rodent species, including rats (6).
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Peripheral Arterial Function in Infants and Young Children With One-Ventricle Physiology and Hypoxemia
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Despite upregulation of nitric oxide, endothelium-dependent vasodilation is blunted in cyanotic adults with Eisenmenger syndrome.16 Upregulation of ET-1 in the lung occurs in chronic hypoxemia, leading to downregulation of nitric oxide and pulmonary vasoconstriction.17,18 The significant differences in FMD and ET-1 in our hypoxemic subjects with 1V physiology compared with our normoxemic subjects with 2V physiology lends evidence for hypoxemia's relation to impaired vasodilation.
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Oxidative and nitrosative stress in pediatric pulmonary hypertension: Roles of endothelin-1 and nitric oxide

Abstract

Section snippets

Endothelin-1 and nitric oxide: key regulators of pulmonary vascular resistance

Endothelin-1 and oxidative stress

Interplay between oxidative and nitrosative stress

Pediatric pulmonary hypertension and endothelial dysfunction

Nitric oxide-cGMP augmentation

Summary and future directions

Acknowledgments

Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia

J. Clin. Invest.

Cloning and expression of a cDNA encoding an endothelin receptor

Nature

Expression and developmental profile of antioxidant enzymes in human lung and liver

Am. J. Respir. Cell Mol. Biol.

Rebound pulmonary hypertension after inhalation of nitric oxide

Ann. Thorac. Surg.

Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms

Physiol. Rev.

Coordinated regulation of genes of the nitric oxide and endothelin pathways during the development of pulmonary hypertension in fetal lambs

Pediatr. Res.

Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension

Am. J. Physiol.

Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide

J. Clin. Invest.

Circulatory effects of endothelin in newborn piglets

Am. J. Physiol.

Augmentation of hypoxic pulmonary vasoconstriction in the isolated perfused rat lung by in vitro antagonists of endothelium-dependent relaxation

J. Clin. Invest.

The overexpression of copper-zinc superoxide dismutase protects NOS III from nitric oxide-mediated inhibition

DNA Cell Biol.

The overexpression catalase reduces NO-mediated inhibition of endothelial NO synthase

IUBMB Life

Increased superoxide generation is associated with pulmonary hypertension in fetal lambs: a role for NADPH oxidase

Circ. Res.

Nitric oxide activates p21ras and leads to the inhibition of endothelial NO synthase by protein nitration

DNA Cell Biol.

Overexpression of human catalase inhibits proliferation and promotes apoptosis in vascular smooth muscle cells

Circ. Res.

Endothelial dysfunction in cardiovascular disease: the role of oxidant stress

Circ. Res.

The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases

Trends Pharmacol. Sci.

Tone-dependent responses to endothelin in isolated perfused fetal sheep pulmonary circulation in situ

J. Appl. Physiol.

Impairment of endothelium-dependent pulmonary artery relaxation in children with congenital heart disease and abnormal pulmonary hemodynamics

Circulation

Reactive oxygen species mediate cyclic strain-induced endothelin-1 gene expression via Ras/Raf/extracellular signal-regulated kinase pathway in endothelial cells

J. Mol. Cell. Cardiol.

An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension

N. Engl. J. Med.

Oxidation–reduction-sensitive binding of lung protein to rat catalase mRNA

J. Biol. Chem.

Rat lung antioxidant enzymes: differences in perinatal gene expression and regulation

Am. J. Physiol.

Reactive oxygen species as downstream mediators of angiogenic signaling by vascular endothelial growth factor receptor-2/KDR

J. Biol. Chem.

Life-threatening effects of discontinuing inhaled nitric oxide in children

Acta Pediatr.

A randomized, controlled study of the 1-hour and 24-hour effects of inhaled nitric oxide therapy in children with acute hypoxemic respiratory failure

Chest

Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group

Crit. Care Med.

Impairment of pulmonary endothelium-dependent relaxation in patients with Eisenmenger's syndrome

Br. J. Pharmacol.

Multicenter randomized controlled trial of the effects of inhaled nitric oxide therapy on gas exchange in children with acute hypoxemic respiratory failure

J. Pediatr.

Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide

Circ. Res.

Receptor-regulated dynamic S-nitrosylation of endothelial nitric-oxide synthase in vascular endothelial cells

J. Biol. Chem.

Role of endothelin-1 in lung disease

Respir. Res.

Regulation of pulmonary vascular tone in the perinatal period

Annu. Rev. Physiol.

Preparation for birth into an O2-rich environment: the antioxidant enzymes in the developing rabbit lung

Pediatr. Res.

Clearance of circulating endothelin-1 by ETB receptors in rats

Biochem. Biophys. Res. Commun.

Nitric oxide activates p21^ras and leads to the inhibition of endothelial NO synthase by protein nitration

Preparation for birth into an O₂-rich environment: the antioxidant enzymes in the developing rabbit lung