A novel mechanism for pulmonary arterial hypertension?

Abstract

HomeCirculationVol. 108, No. 12A Novel Mechanism for Pulmonary Arterial Hypertension? Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBA Novel Mechanism for Pulmonary Arterial Hypertension? John P. Cooke John P. CookeJohn P. Cooke From the Program in Vascular Medicine and Biology, Stanford University School of Medicine, Stanford, Calif. Search for more papers by this author Originally published23 Sep 2003https://doi.org/10.1161/01.CIR.0000087153.11050.ABCirculation. 2003;108:1420–1421The pathophysiology of primary pulmonary hypertension (PPH) involves alterations in vascular reactivity, vascular structure, and interactions of the vessel wall with circulating blood elements.1 An imbalance of vasodilator and vasoconstrictor influences is likely to be an early derangement. Progressive intimal and medial thickening, due to proliferation and migration of vascular smooth muscle cells and fibroblasts, reduces the cross-sectional area of the pulmonary microvasculature, causing fixed alterations in pulmonary resistance. Contributing to the progressive increase in pulmonary resistance is thrombosis of the small pulmonary vessels, which explains the benefit of anticoagulation in these patients. In advanced disease, “plexiform arteriopathy” of the small pulmonary vessels is observed. These lesions proliferate into the lumen, creating high-resistance, convoluted endoluminal channels. There is some controversy regarding the nature of the cells constituting these lesions, one group suggesting they are of endothelial origin, whereas more recent evidence indicates that they are myofibroblasts.2,3See p 1493The normal pulmonary endothelium maintains a low vascular resistance, suppresses vascular smooth muscle growth, inhibits platelet adherence and aggregation, and stems inflammation. In patients with PPH, the endothelium has lost these vasoprotective functions.1 The endothelium of the PPH patient is characterized by the increased elaboration of vasoconstrictors, mitogens, and prothrombotic and proinflammatory mediators (such as thromboxane, endothelin, plasminogen activator inhibitor, and 5-lipooxygenase). These endothelial alterations promote the pathophysiology of PPH. Furthermore, there is less influence of the countervailing factors prostacyclin and NO.Role of NO Synthase Expression and ActivityEndothelium-derived NO plays a critical role in pulmonary vascular homeostasis. The pathological changes that occur in pulmonary hypertension are in part due to impaired bioactivity and/or synthesis of vascular NO. The mechanisms of this impairment are undoubtedly multifactorial and may vary from patient to patient. For example, endothelial NO synthase (NOS) expression has been reported to be decreased, unchanged, or increased in patients with severe pulmonary hypertension.4–6 However, patients with PPH have low levels of NO in their exhaled breath, and endothelium-dependent vasodilation to acetylcholine is impaired.7,8 An impairment of NOS activity in the face of normal or increased NOS expression can be explained if the NOS enzyme was dysfunctional. In hypoxia-induced pulmonary hypertension in rats, NOS activity is inhibited by abnormal coupling with caveolin, which is known to prevent NOS activation.9 In fetal lambs, experimentally induced pulmonary hypertension is in part due to reduced association of HSP 90 with endothelial NOS.10 A different mechanism of impaired NOS activity has been proposed in the pulmonary hypertension associated with sickle cell disease. In addition to elevated plasma levels of cell-free hemoglobin that can scavenge NO,11 patients with sickle cell disease have increased plasma levels of arginase.12 Arginase converts arginine to ornithine and urea, limiting the availability of the NO precursor.13 In patients with sickle cell disease, the increased arginase activity may reduce pulmonary NOS conversion of arginine to NO. If so, supplementary arginine could theoretically reverse this abnormality. Indeed, oral arginine supplementation has been shown to reduce pulmonary pressures in these patients by ≈15 mm Hg.13Low plasma l-arginine concentrations may also contribute to persistent pulmonary hypertension of the newborn, which is also associated with reduced levels of plasma nitrogen oxides.14,15l-Arginine infusion has decreased pulmonary vascular resistance and improved blood oxygenation in infants with this disease process.16DDAH and the NOS PathwayIn this issue of Circulation, Millat et al17 highlight another mechanism that may contribute to reduced NO synthesis in PPH. In a rodent model of chronic hypoxia-induced pulmonary hypertension, Millat et al17 find that the pulmonary vascular expression of endothelium-derived NOS is increased 2-fold. By contrast, there is a significant decline in the NO content of the lung extracts from hypoxic mice. These discordant observations are resolved by their finding that there is a >2-fold increase in lung tissue levels of the endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA; see below). Millat and colleagues hypothesized that the increase in ADMA might be related to a dysregulation of dimethylarginine dimethylaminohydrolase (DDAH) the enzyme that metabolizes ADMA. Accordingly, they assessed pulmonary expression of DDAH by Western analysis and also measured DDAH enzyme activity in pulmonary homogenates. These studies revealed significant reductions in DDAH expression and activity in the rats with pulmonary artery hypertension. The observations of Millat et al17 are consistent with an earlier observation that DDAH expression and activity is reduced in an experimental model of hypoxia-induced pulmonary hypertension.18A similar mechanism may be at work in pulmonary hypertension in humans. l-Arginine supplementation improves pulmonary artery pressures and hemodynamics in patients with primary and secondary pulmonary hypertension.8,19 Finally, it has recently been observed that plasma ADMA levels are elevated in individuals with pulmonary hypertension due to congenital heart disease.20 These studies provided the impetus for a large, randomized clinical trial of arginine therapy for pulmonary hypertension that is underway in Europe and North America.ADMA: An Endogenous Inhibitor of Endothelium-Derived NOSAccumulating evidence indicates that ADMA is an important regulator of endothelial NOS activity (for review, see Cooke21). ADMA is derived from the catabolism of proteins containing methylated arginine residues (as is monomethylarginine, a less common species of NOS inhibitor that has the same effect and metabolic fate as ADMA). Subsequently, ADMA is excreted in the urine or metabolized by DDAH. In renal failure, high plasma levels of ADMA contribute to the severe endothelial dysfunction observed in this disorder. Elevated plasma levels of ADMA may contribute to the endothelial vasodilator dysfunction observed in hypercholesterolemia, hypertension, diabetes mellitus, insulin resistance, hyperhomocystinemia, and vascular disease. Indeed, we propose that ADMA acts as a transducer by which these conditions impair the NOS pathway. We have shown that risk factors for cardiovascular disease elevate plasma ADMA levels by increasing its accumulation. Specifically, each of these risk factors for cardiovascular disease is associated with endothelial oxidative stress and inactivation of DDAH, thereby reducing the metabolism of ADMA.Therapeutic Manipulation of the NOS Pathway for Pulmonary HypertensionCurrently, administration of NO gas is probably the most effective and specific therapy for PPH.22 However, NO gas can generate toxic free radicals and oxides of NO, and technical difficulties have also limited its widespread use. Another approach is to boost the effect of endogenous NO by the administration of oral or inhaled sildenafil. Sildenafil is a cGMP phosphodiesterase inhibitor that augments the action of endogenous NO by reducing the breakdown of its second messenger, cGMP. This agent has been shown to reduce pulmonary pressures and improve symptoms in patients with primary and secondary pulmonary hypertension.23,24 Another approach is to administer NO donors by inhalation; these are under development. Gene transfer of NOS has successfully reduced pulmonary pressures in animal models,25 but viral or cell vectors need to be improved to reduce inflammation and to provide persistent and regulated expression of NOS. Another approach may be to increase DDAH activity or expression so as to reduce circulating levels of the NOS inhibitor. Increased NO synthesis and bioactivity would be expected to acutely reduce pulmonary pressures by its effects on vasoreactivity and to chronically reduce the progression of disease as a result of the inhibition by NO of medial hypertrophy, intimal hyperplasia, and thrombosis. Accordingly, restoration of endogenous NOS activity in the pulmonary endothelium is a therapeutic avenue worthy of further exploration.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, Stanford University School of Medicine, Falk Cardiovascular Research Center, 300 Pasteur Dr, Stanford, CA 94305-5406. E-mail [email protected] References 1 Granton JT, Rabinovitch M. Pulmonary arterial hypertension in congenital heart disease. Cardiol Clin. 2002; 20: 441–457.CrossrefMedlineGoogle Scholar2 Tuder RM, Groves B, Badesch DB, et al. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994; 144: 275–285.MedlineGoogle Scholar3 Yi ES, Kim H, Ahn H, et al. Distribution of obstructive intimal lesions and their cellular phenotypes in chronic pulmonary hypertension: a morphometric and immunohistochemical study. Am J Respir Crit Care Med. 2000; 162: 1577–1586.CrossrefMedlineGoogle Scholar4 Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995; 333: 214–221.CrossrefMedlineGoogle Scholar5 Tuder RM, Cool CD, Geraci MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999; 159: 1925–1932.CrossrefMedlineGoogle Scholar6 Xue C, Johns RA. Endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995; 333: 1642–1644.CrossrefMedlineGoogle Scholar7 Kaneko FT, Arroliga AC, Dweik RA, et al. Biochemical reaction products of nitric oxide as quantitative markers of primary pulmonary hypertension. Am J Respir Crit Care Med. 1998; 158: 917–923.CrossrefMedlineGoogle Scholar8 Mehta S, Stewart DJ, Langleben D, et al. Short-term pulmonary vasodilation with l-arginine in pulmonary hypertension. Circulation. 1995; 92: 1539–1545.CrossrefMedlineGoogle Scholar9 Murata T, Sato K, Hori M, et al. Decreased endothelial nitric-oxide synthase (eNOS) activity resulting from abnormal interaction between eNOS and its regulatory proteins in hypoxia-induced pulmonary hypertension. J Biol Chem. 2002; 277: 44085–44092.CrossrefMedlineGoogle Scholar10 Konduri GG, Ou J, Shi Y, et al. Decreased association of HSP90 impairs endothelial nitric oxide synthase in fetal lambs with persistent pulmonary hypertension. Am J Physiol Heart Circ Physiol. 2003; 285: H204–H211.CrossrefMedlineGoogle Scholar11 Reiter CD, Wang X, Tanus-Santos JE, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle cell disease. Nat Med. 2002; 8: 1383–1389.CrossrefMedlineGoogle Scholar12 Morris CR, Morris SM, Hagar W, et al. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med. 2003; 168: 63–69.CrossrefMedlineGoogle Scholar13 Mori M, Gotoh T. Regulation of nitric oxide production by arginine metabolic enzymes. Biochem Biophys Res Commun. 2000; 275: 715–719.CrossrefMedlineGoogle Scholar14 Vosatka R, Kashyap S, Trifiletti R. Arginine deficiency accompanies persistent pulmonary hypertension of the newborn. Biol Neonate. 1994; 66: 65–70.CrossrefMedlineGoogle Scholar15 Pearson D, Dawling S, Walsh W, et al. Neonatal pulmonary hypertension–urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med. 2001; 344: 1832–1838.CrossrefMedlineGoogle Scholar16 McCaffrey M, Bose C, Reiter P, Stiles A. Effect of l-arginine infusion on infants with persistent pulmonary hypertension of the newborn. Biol Neonate. 1995; 67: 240–243.CrossrefMedlineGoogle Scholar17 Millat LJ, Whitley GSJ, Li D, et al. Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia–induced pulmonary hypertension. Circulation. 2003; 108: 1493–1498.LinkGoogle Scholar18 Arrigoni FI, Vallance P, Haworth SG, et al. Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia. Circulation. 2003; 107: 1195–1201.LinkGoogle Scholar19 Nagaya N, Uematsu M, Oya H, et al. Short-term oral administration of l-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension. Am J Respir Crit Care Med. 2001; 163: 887–891.CrossrefMedlineGoogle Scholar20 Gorenflo M, Zheng C, Werle E, et al. Plasma levels of asymmetrical dimethyl-l-arginine in patients with congenital heart disease and pulmonary hypertension. J Cardiovasc Pharmacol. 2001; 37: 489–492.CrossrefMedlineGoogle Scholar21 Cooke JP. Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol. 2000; 20: 2032–2037.CrossrefMedlineGoogle Scholar22 Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997; 336: 111–117.CrossrefMedlineGoogle Scholar23 Ghofrani HA, Wiedemann R, Rose F, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med. 2002; 136: 515–522.CrossrefMedlineGoogle Scholar24 Wilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation. 2001; 104: 1218–1222.CrossrefMedlineGoogle Scholar25 Champion HC, Bivalacqua TJ, Greenberg SS, et al. Adenoviral gene transfer of endothelial nitric-oxide synthase (eNOS) partially restores normal pulmonary arterial pressure in eNOS-deficient mice. Proc Natl Acad Sci U S A. 2002; 99: 13248–13253.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Türer Cabbar A, Değertekin M, Şimşek M, Özveren O, Güleç S, Yanartaş M, Gezer Taş S, Olgun Yıldızeli Ş, Mutlu B, İşbir T and Yıldızeli B (2022) Evaluation of Asymmetric Dimethylarginine Levels in Patients With Chronic Thromboembolic Pulmonary Hypertension Undergoing Pulmonary Endarterectomy, Heart, Lung and Circulation, 10.1016/j.hlc.2021.05.090, 31:1, (110-118), Online publication date: 1-Jan-2022. Lee H, Yeom A, Kim K and Hong Y (2019) Effect of Ambrisentan Therapy on the Expression of Endothelin Receptor, Endothelial Nitric Oxide Synthase and NADPH Oxidase 4 in Monocrotaline-induced Pulmonary Arterial Hypertension Rat Model, Korean Circulation Journal, 10.4070/kcj.2019.0006, 49:9, (866) Lüneburg N, Siques P, Brito J, Arriaza K, Pena E, Klose H, Leon-Velarde F and Böger R (2016) Long-Term Chronic Intermittent Hypobaric Hypoxia in Rats Causes an Imbalance in the Asymmetric Dimethylarginine/Nitric Oxide Pathway and ROS Activity: A Possible Synergistic Mechanism for Altitude Pulmonary Hypertension?, Pulmonary Medicine, 10.1155/2016/6578578, 2016, (1-9), . Lüneburg N, Harbaum L and Hennigs J (2014) The Endothelial ADMA/NO Pathway in Hypoxia-Related Chronic Respiratory Diseases, BioMed Research International, 10.1155/2014/501612, 2014, (1-11), . Rhodes C, Abdul-Salam V, Wharton J and Wilkins M (2011) Blood biomarkers Pulmonary Circulation, 3rd edition, 10.1201/b13219-15, (146-158), Online publication date: 27-May-2011. Altuntaş M, Atalay F, Can M, Altın R and Tor M (2011) Serum Asymmetric Dimethylarginine, Nitrate, Vitamin B 12 , and Homocysteine Levels in Individuals with Pulmonary Embolism , Mediators of Inflammation, 10.1155/2011/215057, 2011, (1-6), . Wójcik E, Gromkowska M, Masłowska E, Gamian E and Pellar J (2008) Aktywność dysmutazy ponadtlenkowej u dzieci z wrodzonymi wadami serca, Pediatria Polska, 10.1016/S0031-3939(08)70266-X, 83:2, (114-120), Online publication date: 1-Mar-2008. Anaid Shahbazian , Petkov V, Baykuscheva-Gentscheva T, Hoeger H, Painsipp E, Holzer P and Mosgoeller W (2007) Involvement of endothelial NO in the dilator effect of VIP on rat isolated pulmonary artery, Regulatory Peptides, 10.1016/j.regpep.2006.10.012, 139:1-3, (102-108), Online publication date: 1-Mar-2007. Stephens C and Fawcett T (2007) Nitric oxide and nursing: a review, Journal of Clinical Nursing, 10.1111/j.1365-2702.2005.01527.x, 16:1, (67-76), Online publication date: 1-Jan-2007. Lemus-Varela M, Sola A, Gómez-Meda B, Zamora-Perez A, Ramos-Ibarra M, Batista-González C and Zúñiga-González G (2006) Oral sildenafil citrate lacks genotoxicity and cytotoxicity in a primate model: Callithrix jacchus, Journal of Perinatology, 10.1038/sj.jp.7211518, 26:7, (423-427), Online publication date: 1-Jul-2006. Kawaguchi Y, Tochimoto A, Hara M, Kawamoto M, Sugiura T, Katsumata Y, Okada J, Kondo H, Okubo M and Kamatani N (2006) NOS2 polymorphisms associated with the susceptibility to pulmonary arterial hypertension with systemic sclerosis: contribution to the transcriptional activity, Arthritis Research & Therapy, 10.1186/ar1984, 8:4, (R104), . Kielstein J, Bode-Böger S, Hesse G, Martens-Lobenhoffer J, Takacs A, Fliser D and Hoeper M (2005) Asymmetrical Dimethylarginine in Idiopathic Pulmonary Arterial Hypertension, Arteriosclerosis, Thrombosis, and Vascular Biology, 25:7, (1414-1418), Online publication date: 1-Jul-2005. September 23, 2003Vol 108, Issue 12 Advertisement Article InformationMetrics https://doi.org/10.1161/01.CIR.0000087153.11050.ABPMID: 14504250 Originally publishedSeptember 23, 2003 KeywordsEditorialsendotheliumhypertension, pulmonarynitric oxide synthasePDF download Advertisement