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A Potent Pathogenic Mediator in Pulmonary Arterial Hypertension |
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ET is a 21-amino acid peptide produced primarily by vascular endothelial cells.1 |
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Endothelin (ET), a neurohormonal mediator produced by the endothelium, is overproduced in pulmonary arterial hypertension (PAH), a devastating and rapidly progressing disease.1 This excess ET is associated with structural changes in the pathology of PAH vasculature, including inflammation,1 vasoconstriction,2 cell proliferation,2 and fibrosis.1 Left untreated, PAH patients have an estimated 5-year survival rate of 34%.3 |
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Endothelin in PAH4 |
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*Statements are based on observations reported from in vitro or animal trials.
The clinical significance in humans is unknown. |
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Two Receptors Mediate the Effects of ET*
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ET has a strong affinity for 2 receptors (ETA and ETB), which are located on the endothelial cells, smooth muscle cells, fibroblasts, and numerous other cell types throughout the body.5,6 The 2 receptors have similar but distinct activities in pathology.7 |
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Here we see ET binding to its two receptors on vascular smooth muscle cells. This action causes contraction, cellular proliferation, and vasoconstriction.1,2 |
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*Statements are based on observations reported from in vitro or animal trials.
The clinical significance in humans is unknown. |
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REFERENCES |
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1. |
Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732–1739. |
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2. |
Rich S, McLaughlin VV. Pulmonary hypertension. In: Libby P, Bonow RO, Mann DL, Zipes DE. Braunwald's Heart Disease. 2 vols. 8th ed. Philadelphia, PA: Saunders Elsevier; 2008:1883–1914. |
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3. |
D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343–349. |
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4. |
Kim NH, Rubin LJ. Endothelin in health and disease: endothelin receptor antagonists in the management of pulmonary artery hypertension. J Cardiovasc Pharmacol Ther. 2002;7:9–19. |
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5. |
Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol. 2001;41:851–876. |
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6. |
Katwa LC, Guarda E, Weber KT. Endothelin receptors in cultured adult rat cardiac fibroblasts. Cardiovasc Res. 1993:27:2125–2129. |
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7. |
Goraca A. New views on the role of endothelin. Endocr Regul. 2002;36:161–167. |
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8. |
Davie N, Haleen SJ, Upton PD, et al. ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care
Med. 2002;165:398–405. |
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9. |
Muller DN, Mervaala EM, Schmidt F, et al. Effect of bosentan on NF-kappaB, inflammation, and tissue factor in angiotensin II-induced end-organ damage. Hypertension. 2000;36:282–209. |
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10. |
Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol. 1999;61:391–415. |
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