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