PRE-CLINICAL RESEARCH: EDITORIAL COMMENT
Endothelin and the Systemic CirculationA Therapeutic Target Worth Revisiting?*
Lewis J. Rubin, MD*
University of California, San Diego, La Jolla, California
* Reprint requests and correspondence: Dr. Lewis J. Rubin, UCSD Medical Center, 9300 Campus Point Drive, M/C 7372, La Jolla, California 92037 (Email: ljrubin{at}ucsd.edu).
Key Words: obstructive sleep apnea • myocardial infarction • hypoxia inducible factor-1 • gene expression • endothelin
Endothelin (ET)-1, one of the most potent endogenous vasoconstrictors and promoters of vascular growth, is produced by vascular endothelial cells in response to a variety of stimuli (1,2). The development of ET receptor antagonists (3) facilitated the exploration of the pathophysiological role of ET-1 in a variety of diseases in which ET-1 expression is increased, including systemic hypertension (4), congestive heart failure (5), Raynaud's phenomenon and digital ulcers in scleroderma (6), pulmonary arterial hypertension (7), and idiopathic pulmonary fibrosis (8). Despite large-scale clinical trials in these conditions, ET receptor antagonists have been demonstrated to have convincing clinical effects only in pulmonary arterial hypertension, the sole condition for which both the dual ET-A and ET-B receptor antagonist bosentan and the more selective ET-A receptor antagonist ambrisentan have received approval by the Food and Drug Administration. In this issue of the Journal, Belaidi et al. (9) provide evidence that ET-1 may play a more significant role in the systemic circulation under certain conditions, specifically intermittent hypoxia in the background of a predisposition for systemic hypertension, and suggest that the clinical scenario that they sought to mimic in their studies—obstructive sleep apnea (OSA)—may benefit from therapy with ET receptor antagonists.
Belaidi et al. (9) exposed control and spontaneously hypertensive rats to intermittent hypoxia designed to mimic the frequent intervals of apnea that are experienced by individuals with severe, uncontrolled OSA, and found that the spontaneously hypertensive rats, but not control rats, manifested greater increases in blood pressure and coronary vasoreactivity along with increased expression of ET-1 and hypoxia-inducible transcription factor (HIF)-1. In addition, the administration of bosentan blocked these augmented systemic vascular responses. They suggest that HIF-1 mediates the increased ET-1 expression in their model.
OSA is a common disorder that has been increasingly recognized as a significant contributing factor to cardiovascular morbidity and mortality, including both systemic hypertension and heart failure (10,11). Although lifestyle changes, such as weight loss and avoidance of alcohol and other sedatives, are effective in some patients with OSA, these are not always contributory factors, and other active measures for management are often needed. Continuous positive airway pressure applied at night is an effective, albeit cumbersome, therapy for OSA that, when adjusted to the patient's individual requirements and used consistently, effectively reverses nocturnal hypoxemia and may reduce the comorbid cardiovascular events. Technological advances in this field have improved the diagnostic approach to OSA as well as patient comfort and compliance with the hardware used for its treatment. It is unlikely, therefore, that, given the expense and toxicities of ET receptor antagonists, these agents will have much advantage over current therapy for OSA, although studies in OSA patients who have persistent cardiovascular comorbidities despite continuous positive airway pressure therapy may be of potential interest. Perhaps more worthy of study are other conditions in which intermittent hypoxia coexists with systemic vascular disease, notably the aging population with smoking-related chronic obstructive pulmonary disease and coexistent systemic hypertension or arteriosclerotic heart disease: while an extrapolation from the studies of Belaidi et al. (9) to this clinical condition is equally fraught with limitations, the medical need is considerable and the rationale is strengthened by their findings.
The experiments presented by Belaidi et al. (9) provide evidence that HIF-1 and ET-1 interact in experimental conditions that are related, but not identical, to human disease. Whether this observation will translate to a new therapeutic target for ET receptor antagonists is unclear, but it at least provides a rationale for exploring the effects of these drugs in relevant populations for which novel approaches to therapy are needed.
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Footnotes
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Dr. Rubin has served as a consultant and investigator for Actelion, Gilead, and Pfizer.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells Nature 1988;332:411-415.[CrossRef][Medline]2. Takuwa N, Takuwa Y, Yanagisawa M, Yamashita K, Masaki T. A novel vasoactive peptide endothelin stimulates mitogenesis through inositol lipid turnover in Swiss 3T3 fibroblasts J Biol Chem 1989;264:7856-7861.[Abstract/Free Full Text] 3. Motte S, McEntee K, Naeije R. Endothelin receptor antagonists Pharmacol Ther 2006;110:386-414.[CrossRef][Web of Science][Medline] 4. Krum H, Viskoper RJ, Lacourciere Y, Budde M, Charlon V. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension N Engl J Med 1998;338:784-790.[CrossRef][Web of Science][Medline] 5. O'Connor CM, Gattis WA, Adams KF, et al. Tezosentan in patients with acute heart failure and acute coronary syndromes—results of the Randomized Intravenous Tezosentan study (RITZ-4) J Am Coll Cardiol 2003;41:1452-1457.[Abstract/Free Full Text] 6. Korn JH, Mayes M, Cerinic MM, et al. Digital ulcers in systemic sclerosis—prevention by treatment with bosentan, an oral endothelin receptor antagonist Arthritis Rheum 2004;50:3985-3993.[CrossRef][Web of Science][Medline] 7. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension N Engl J Med 2002;346:896-903.[CrossRef][Web of Science][Medline] 8. King TE, Behr J, Brown KK, et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis Am J Respir Crit Care Med 2008;177:75-81.[Abstract/Free Full Text] 9. Belaidi E, Joyeux-Faure M, Ribuot C, Launois SH, Levy P, Godin-Ribuot D. Major role for hypoxia inducible factor-1 and the endothelin system in promoting myocardial infarction and hypertension in an animal model of obstructive sleep apnea J Am Coll Cardiol 2009;53:1309-1317.[Abstract/Free Full Text] 10. Parish JM, Somers VK. Obstructive sleep apnea and cardiovascular disease Mayo Clin Proc 2004;7:1036-1046. 11. Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease JAMA 2003;290:1906-1914.[Abstract/Free Full Text]
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