From arginine methylation to ADMA: A novel mechanism with therapeutic potential in chronic lung diseases
© Zakrzewicz and Eickelberg; licensee BioMed Central Ltd. 2009
Received: 30 October 2008
Accepted: 29 January 2009
Published: 29 January 2009
Protein arginine methylation is a novel posttranslational modification regulating a diversity of cellular processes, including protein-protein interaction, signal transduction, or histone function. It has recently been shown to be dysregulated in chronic renal, vascular, and pulmonary diseases, and metabolic products originating from protein arginine methylation have been suggested to serve as biomarkers in cardiovascular and pulmonary diseases.
Protein arginine methylation is performed by a class of enzymes called protein arginine methyltransferases (PRMT), which specifically methylate protein-incorporated arginine residues to generate protein-incorporated monomethylarginine (MMA), symmetric dimethylarginine (SDMA), or asymmetric dimethylarginine (ADMA). Upon proteolytic cleavage of arginine-methylated proteins, free intracellular MMA, SDMA, or ADMA is generated, which, upon secretion into the extracellular space (including plasma), directly affects the methylarginine concentration in the plasma. Free methylarginines are cleared from the body by renal excretion or hepatic metabolism. In addition, MMA and ADMA, but not SDMA, can be degraded via a class of intracellular enzymes called dimethylarginine dimethylaminohydrolases (DDAH).
ADMA and MMA are endogenous inhibitors of nitric oxide synthases (NOS) and ADMA has been suggested to serve as a biomarker of endothelial dysfunction in cardiovascular diseases. This view has now been extended to the idea that, in addition to serum ADMA, the amount of free, as well as protein-incorporated, intracellular ADMA influences pulmonary cell function and determines the development of chronic lung diseases, including pulmonary arterial hypertension (PAH) or pulmonary fibrosis. This review will present and discuss the recent findings of dysregulated arginine methylation in chronic lung disease. We will highlight novel directions for future investigations evaluating the functional contribution of arginine methylation in lung homeostasis and disease with the outlook that modifying PRMT or DDAH activity presents a novel therapeutic option for the treatment of chronic lung disease.
A brief introduction to protein arginine methylation
During the last 40 years, arginine methylation has been extensively studied in prokaryotes and eukaryotes, revealing a pivotal role of this posttranslational modification in the regulation of a number of cellular processes. Protein arginine methylation is involved in the modulation of transcription, RNA metabolism, or protein-protein interaction, thereby controlling cellular differentiation, proliferation, survival, or apoptosis [1, 2].
Free methylarginines are cleared from the body by renal excretion and hepatic metabolism [3, 4]. In addition, MMA and ADMA, but not SDMA, can be degraded to citrulline and mono- or dimethylamines, respectively, by dimethylarginine dimethylaminohydrolases (DDAH) . To date, two DDAH isoforms have been cloned and characterized, termed DDAH1 and DDAH2 . Alternatively, ADMA can also be converted to α-keto valeric acid by alanine:glyoxylate aminotransferase 2 , although the influence of this pathway on total ADMA metabolism has not been extensively studied thus far. Of interest, the demethylation/clearance of methylarginines is restricted to free methylarginines, as a theoretically possible demethylation of protein-incorporated, methylated L-Arg residues in situ has yet not been demonstrated. It should be noted, however, that the conversion of protein-incorporated MMA to citrulline by peptidylarginine deiminase 4 was recently demonstrated, which prevented histone methylation by PRMT 1 and 4 [7, 8]. This may influence protein methylation directly, as MMA deimination will decrease the amount of protein-incorporated MMA that is available for dimethylation by PRMT, but the relevance of protein deimination of protein-incorporated MMA by PAD enzymes has also been challenged lately [9, 10]. Finally, free SDMA has been described to be catabolized in vivo when injected intraperitoneally into rats, although the enzymes involved have thus far not been identified .
ADMA has been detected in urine, plasma, cerebrospinal and bronchoalveolar lavage (BAL) fluids, and various types of tissues [3, 4, 12, 13]. Specific methylation of protein-incorporated L-Arg residues was originally described in 1968 , but the key finding that ADMA is a potent inhibitor of all three nitric oxide synthase (NOS) isoforms (nNOS, iNOS, and eNOS), resulting in impaired NO production in vitro and in vivo, was only reported in 1992 by Vallance et al. . NO is a well-known vasodilator that essentially controls a diverse range of pulmonary functions, such as macrophage activity, pulmonary artery vasodilation, or bronchoconstriction . ADMA may therefore control pulmonary cell functions either via direct effects on gene expression and protein function, as recently shown in an elegant study , or via inhibition of NOS and subsequently altered NO generation. Furthermore, the lung generates a significant amount of ADMA itself, and as such may directly contribute to interstitial and plasma ADMA levels , further suggesting that dysregulated ADMA metabolism in the lung may trigger, initiate, or perpetuate chronic lung diseases, such as pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), asthma, or chronic obstructive pulmonary disease (COPD). In the following, we will outline the current evidence of dysregulated protein arginine methylation or ADMA levels in specific lung diseases.
Arginine methylation in pulmonary arterial hypertension
Pulmonary arterial hypertension (PAH) is a fatal syndrome characterized by an elevated blood pressure in the pulmonary circulation, due to increased resistance of pulmonary arterioles . The pathophysiology of PAH includes endothelial dysfunction and pulmonary arterial smooth muscle cell (PASMC) hypertrophy and proliferation . Elevated ADMA concentrations have been detected in the plasma of patients with idiopathic (I)PAH [21–23], chronic thromboembolic pulmonary hypertension (CTEPH) , or PAH related to sickle cell disease  or systemic sclerosis , suggesting a strong association of circulating methylarginine levels with PAH pathogenesis. A recent study by Xu et al., however, detected increased arginase activity in the serum of PAH patients, whereas serum ADMA levels did not differ between PAH patients and healthy individuals, suggesting that increased arginase activity was responsible for endothelial dysfunction observed in PAH . This is of particular interest, as arginase directly metabolizes free L-Arg. Increased arginase activity as well as ADMA content was subsequently confirmed in pulmonary arterial endothelial cells in the rat model of monocrotaline-induced pulmonary hypertension .
The investigation of animal models of PAH, using e.g. chronic hypoxia or the pyrrolizidine alkaloid monocrotaline to induce PAH in piglets, mice, or rats, have largely detected increased plasma ADMA during the development of experimental PAH, but have thus far suggested different mechanisms responsible for this increase. While some groups have reported decreased DDAH1 expression along with increased ADMA levels [28, 29], others have detected decreased DDAH2 in this condition [22, 30]. Most importantly, the analysis of lung tissues obtained from IPAH or control patients have demonstrated an impaired expression of DDAH2, but not DDAH1, in IPAH . Furthermore, PRMT expression was found to be upregulated in mice exposed to chronic hypoxia, resulting in increased ADMA tissue levels and a decreased L-Arg/ADMA ratio, thereby supporting an important role of PRMT-mediated ADMA generation in hypoxia-induced PAH .
In sum, disrupted methylarginine metabolism most likely impairs vascular homeostasis in PAH, but it remains unclear, which DDAH or PRMT isoforms control ADMA tissue and plasma levels under pathological conditions. Further, the relative contributions of serum, interstitial, or pulmonary ADMA levels to PAH pathogenesis remain unclear, as comparative investigations are still lacking. Data obtained in transgenic mice with manipulation of DDAH expression have thus far supported a major role for DDAH1 in serum and tissue ADMA homeostasis. Forced overexpression of DDAH-1 in transgenic mice resulted a 2-fold reduction in plasma ADMA levels and decreased blood pressure , while the loss of DDAH-1 activity by homologous recombination in mice led to accumulation of circulating ADMA and increased blood pressure . In contrast, forced overexpression of DDAH2 led only to a 20% reduction in circulating ADMA, but no reduction in systemic blood pressure .
Arginine methylation in pulmonary fibrosis
Compared with the aforementioned available data on ADMA and vascular remodeling in PAH, much less is known about the role of methylated arginines in interstitial remodeling of the lung, e. g. in idiopathic pulmonary fibrosis (IPF). A growing body of evidence, however, suggests that arginine methylation and ADMA metabolism may be involved in the progression of IPF, a lethal disorder of major concern due to its unresolved pathogenesis and limited responsiveness to currently available therapies . The hallmark lesions of IPF are fibroblast foci, which are sites featuring α-smooth muscle actin (αSMA)-positive, activated (myo)fibroblasts that synthesize and deposit a collagen-rich extracellular matrix . Fibroblast foci occur in subepithelial layers adjacent to areas of alveolar epithelial cell injury, suggesting that altered epithelial-mesenchymal crosstalk contributes to the pathobiology of IPF. Indeed, it is well accepted that repetitive alveolar epithelial cell injury and subsequent repair, in the presence or absence of local inflammation, represents a key pathogenic mechanism in IPF [35, 36]. This leads to aberrant growth factor activation and perpetuation of fibrotic transformation. In addition to the well-described cytokines and growth factors interleukin-4, -13, -21, wingless, or transforming growth factor-β, components of the renin-angiotensin-aldosterone system including angiotensin II (ANGII) have recently been identified as important regulators of fibrosis [37, 38].
Arginine methylation in COPD
It has recently been suggested that NO metabolites, reactive oxygen species, and nitrosothiols represent novel targets for the prevention and treatment of chronic inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) [43, 44]. In contrast, little is known about methylarginine metabolism in the pathogenesis of these disorders. Since cigarette smoke represents the main risk factor for COPD, several studies have investigated the relationship between cigarette smoke and ADMA levels, with conflicting results. While some studies have found decreased ADMA levels in smokers compared with non-smokers [45, 46], others have detected increased ADMA levels in smokers, in the absence or presence of triple vessel coronary artery disease [47, 48].
A similar divergence is evident in in vitro studies using cigarette smoke extract (CSE)-treated cell cultures. The exposure of human endothelial cells to 10% CSE decreased intracellular ADMA concentration via increased DDAH2 expression , while others have reported increased ADMA levels under such conditions . In the absence of direct ADMA measurements in COPD or asthma patients, the available data therefore suggests that cigarette smoke is an important regulator of ADMA synthesis, but more conclusive in vivo and in vitro evidence is needed to assess whether COPD or asthma, or pathogenetic aspects thereof, are associated with altered ADMA levels.
The relevance of plasma ADMA levels
A significant debate about the contribution of plasma ADMA to the regulation of NOS-dependent NO production has recently been initiated. In pathological conditions including PH, plasma ADMA levels have been shown to increase to 0.53 ± 0.15 μM (from 0.36 ± 0.05 μM in controls) and 1.06 ± 0.06 μM (from 0.48 ± 0.04 μM) in studies by Kielstein et al. and Pullamsetti et al. [22, 23], respectively. Taking into consideration the physiological plasma levels of L-Arg of 100 μM, the normal plasma ADMA concentrations of 0.42 ± 0.06 μM  must approach approximately 10 μM to elicit a significant effect on NO production and physiological functions thereof in the plasma . It is therefore highly unlikely that plasma ADMA levels significantly contribute to decreased serum NO bioavailability observed in PAH or other cardiovascular disorders. In contrast, intracellular ADMA levels may significantly influence NOS activity under pathological conditions, as these have been shown to increase from 5.8 ± 1.2 μM to 21.6 ± 4.7 μM, for example, in carotid arteries subjected to balloon-induced vascular injury . Increased intracellular ADMA levels may be particularly relevant to lung diseases, as the lung exhibits one of the highest baseline concentrations of intracellular ADMA . Of note, small changes in plasma ADMA may serve as indicators of greater changes in intracellular ADMA. Therefore, further studies should closely investigate alterations of the intracellular methylarginine content in chronic lung disease, a factor that is clearly more likely to modify NO generation. In contrast, altered plasma ADMA levels may rather be a marker of disrupted methylarginine metabolism in selected intracellular compartments rather than a direct cause of structural or functional abnormalities in the cardiovascular system.
In conclusion, dysregulated arginine methylation has now been shown to contribute to the pathogenesis of several pulmonary disorders, in experimental animal models as well as human disease. Causal relationships between dysregulated arginine methylation and the initiation, progression, or therapy of lung disease, however, remain to be dissected. Future investigations of arginine methylation dynamics in these diseases will therefore have to address, among others, the following questions:
1) Which tissues are the source of increased plasma ADMA levels in chronic lung disease?
2) Which specific cell types are the major contributors within a given tissue to altered plasma ADMA levels under pathophysiological conditions?
3) Can dysregulated arginine methylation itself lead to altered lung structure and function?
Future studies will undoubtedly shed light on the relative importance of protein arginine methylation and highlight cellular events that are controlled by posttranslational modification of L-Arg residues under physiological and pathophysiological scenarios. The regulation of methylarginine metabolism by modulating cellular PRMT or DDAH activity will therefore likely present a novel therapeutic option for the treatment of chronic lung diseases such as PAH, IPF, asthma, or COPD.
- Bedford MT, Richard S: Arginine methylation an emerging regulator of protein function. Mol Cell. 2005, 18 (3): 263-272. 10.1016/j.molcel.2005.04.003.View ArticlePubMedGoogle Scholar
- Lee DY, Teyssier C, Strahl BD, Stallcup MR: Role of protein methylation in regulation of transcription. Endocr Rev. 2005, 26 (2): 147-170. 10.1210/er.2004-0008.View ArticlePubMedGoogle Scholar
- Vallance P, Leiper J: Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol. 2004, 24 (6): 1023-1030. 10.1161/01.ATV.0000128897.54893.26.View ArticlePubMedGoogle Scholar
- Leiper JM, Vallance P: The synthesis and metabolism of asymmetric dimethylarginine (ADMA). Eur J Clin Pharmacol. 2006, 62 (Suppl 13): 33-38. 10.1007/s00228-005-0013-y.View ArticleGoogle Scholar
- Closs EI, Basha FZ, Habermeier A, Forstermann U: Interference of L-arginine analogues with L-arginine transport mediated by the y+ carrier hCAT-2B. Nitric Oxide. 1997, 1 (1): 65-73. 10.1006/niox.1996.0106.View ArticlePubMedGoogle Scholar
- Ogawa T, Kimoto M, Sasaoka K: Dimethylarginine:pyruvate aminotransferase in rats. Purification, properties, and identity with alanine:glyoxylate aminotransferase 2. J Biol Chem. 1990, 265 (34): 20938-20945.PubMedGoogle Scholar
- Cuthbert GL, Daujat S, Snowden AW, Erdjument-Bromage H, Hagiwara T, Yamada M, Schneider R, Gregory PD, Tempst P, Bannister AJ, et al: Histone deimination antagonizes arginine methylation. Cell. 2004, 118 (5): 545-553. 10.1016/j.cell.2004.08.020.View ArticlePubMedGoogle Scholar
- Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L, Sonbuchner LS, McDonald CH, Cook RG, Dou Y, et al: Human PAD4 regulates histone arginine methylation levels via demethylimination. Science. 306 (5694): 279-283. 10.1126/science.1101400.Google Scholar
- Raijmakers R, Zendman AJ, Egberts WV, Vossenaar ER, Raats J, Soede-Huijbregts C, Rutjes FP, van Veelen PA, Drijfhout JW, Pruijn GJ: Methylation of arginine residues interferes with citrullination by peptidylarginine deiminases in vitro. J Mol Biol. 2007, 367 (4): 1118-1129. 10.1016/j.jmb.2007.01.054.View ArticlePubMedGoogle Scholar
- Thompson PR, Fast W: Histone citrullination by protein arginine deiminase: is arginine methylation a green light or a roadblock?. ACS Chem Biol. 2006, 1 (7): 433-441. 10.1021/cb6002306.View ArticlePubMedGoogle Scholar
- Ogawa T, Kimoto M, Watanabe H, Sasaoka K: Metabolism of NG,NG-and NG,N'G-dimethylarginine in rats. Arch Biochem Biophys. 1987, 252 (2): 526-537. 10.1016/0003-9861(87)90060-9.View ArticlePubMedGoogle Scholar
- Teerlink T, Nijveldt RJ, de Jong S, van Leeuwen PA: Determination of arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography. Anal Biochem. 2002, 303 (2): 131-137. 10.1006/abio.2001.5575.View ArticlePubMedGoogle Scholar
- Boger RH: Asymmetric dimethylarginine (ADMA) and cardiovascular disease: insights from prospective clinical trials. Vasc Med. 2005, 10 (Suppl 1): S19-25. 10.1191/1358863x05vm602oa.View ArticlePubMedGoogle Scholar
- Paik WK, Kim S: Protein methylase I. Purification and properties of the enzyme. J Biol Chem. 1968, 243 (9): 2108-2114.PubMedGoogle Scholar
- Vallance P, Leone A, Calver A, Collier J, Moncada S: Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992, 339 (8793): 572-575. 10.1016/0140-6736(92)90865-Z.View ArticlePubMedGoogle Scholar
- Dweik RA: The lung in the balance: arginine, methylated arginines, and nitric oxide. Am J Physiol Lung Cell Mol Physiol. 2007, 292 (1): L15-17. 10.1152/ajplung.00322.2006.View ArticlePubMedGoogle Scholar
- Smith CL, Anthony S, Hubank M, Leiper JM, Vallance P: Effects of ADMA upon gene expression: an insight into the pathophysiological significance of raised plasma ADMA. PLoS Med. 2005, 2 (10): e264-10.1371/journal.pmed.0020264.View ArticlePubMedPubMed CentralGoogle Scholar
- Bulau P, Zakrzewicz D, Kitowska K, Leiper J, Gunther A, Grimminger F, Eickelberg O: Analysis of methylarginine metabolism in the cardiovascular system identifies the lung as a major source of ADMA. Am J Physiol Lung Cell Mol Physiol. 2007, 292 (1): L18-24. 10.1152/ajplung.00076.2006.View ArticlePubMedGoogle Scholar
- Ghofrani HA, Wilkins MW, Rich S: Uncertainties in the diagnosis and treatment of pulmonary arterial hypertension. Circulation. 2008, 118 (11): 1195-1201. 10.1161/CIRCULATIONAHA.106.674002.View ArticlePubMedGoogle Scholar
- Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, et al: Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004, 43 (12 Suppl S): 13S-24S. 10.1016/j.jacc.2004.02.029.View ArticlePubMedGoogle Scholar
- Gorenflo M, Zheng C, Werle E, Fiehn W, Ulmer HE: Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension. J Cardiovasc Pharmacol. 2001, 37 (4): 489-492. 10.1097/00005344-200104000-00016.View ArticlePubMedGoogle Scholar
- Pullamsetti S, Kiss L, Ghofrani HA, Voswinckel R, Haredza P, Klepetko W, Aigner C, Fink L, Muyal JP, Weissmann N, et al: Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension. FASEB J. 2005, 19 (9): 1175-1177.PubMedGoogle Scholar
- Kielstein JT, Bode-Boger SM, Hesse G, Martens-Lobenhoffer J, Takacs A, Fliser D, Hoeper MM: Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol. 2005, 25 (7): 1414-1418. 10.1161/01.ATV.0000168414.06853.f0.View ArticlePubMedGoogle Scholar
- Skoro-Sajer N, Mittermayer F, Panzenboeck A, Bonderman D, Sadushi R, Hitsch R, Jakowitsch J, Klepetko W, Kneussl MP, Wolzt M, et al: Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2007, 176 (11): 1154-1160. 10.1164/rccm.200702-278OC.View ArticlePubMedGoogle Scholar
- Landburg PP, Teerlink T, van Beers EJ, Muskiet FA, Kappers-Klunne MC, van Esser JW, Mac Gillavry MR, Biemond BJ, Brandjes DP, Duits AJ, et al: Association of asymmetric dimethylarginine with sickle cell disease-related pulmonary hypertension. Haematologica. 2008, 93 (9): 1410-1412. 10.3324/haematol.12928.View ArticlePubMedGoogle Scholar
- Dimitroulas T, Giannakoulas G, Sfetsios T, Karvounis H, Dimitroula H, Koliakos G, Settas L: Asymmetrical dimethylarginine in systemic sclerosis-related pulmonary arterial hypertension. Rheumatology. 2008, 47 (11): 1682-1685. 10.1093/rheumatology/ken346.View ArticlePubMedGoogle Scholar
- Xu W, Kaneko FT, Zheng S, Comhair SA, Janocha AJ, Goggans T, Thunnissen FB, Farver C, Hazen SL, Jennings C, et al: Increased arginase II and decreased NO synthesis in endothelial cells of patients with pulmonary arterial hypertension. FASEB J. 2004, 18 (14): 1746-1748.PubMedGoogle Scholar
- Sasaki A, Doi S, Mizutani S, Azuma H: Roles of accumulated endogenous nitric oxide synthase inhibitors, enhanced arginase activity, and attenuated nitric oxide synthase activity in endothelial cells for pulmonary hypertension in rats. Am J Physiol Lung Cell Physiol. 2007, 292 (6): L1480-L1487. 10.1152/ajplung.00360.2006.View ArticleGoogle Scholar
- Millatt LJ, Whitley GS, Li D, Leiper JM, Siragy HM, Carey RM, Johns RA: Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension. Circulation. 2003, 108 (12): 1493-1498. 10.1161/01.CIR.0000089087.25930.FF.View ArticlePubMedGoogle Scholar
- Arrigoni FI, Vallance P, Haworth SG, Leiper JM: Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia. Circulation. 2003, 107 (8): 1195-1201. 10.1161/01.CIR.0000051466.00227.13.View ArticlePubMedGoogle Scholar
- Yildirim AO, Bulau P, Zakrzewicz D, Kitowska KE, Weissmann N, Grimminger F, Morty RE, Eickelberg O: Increased protein arginine methylation in chronic hypoxia: role of protein arginine methyltransferases. Am J Respir Cell Mol Biol. 2006, 35 (4): 436-443. 10.1165/rcmb.2006-0097OC.View ArticlePubMedGoogle Scholar
- Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger MC, Wang BY, Tsao PS, Kimoto M, Vallance P, Patterson AJ, et al: Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation. 2003, 108 (24): 3042-3047. 10.1161/01.CIR.0000101924.04515.2E.View ArticlePubMedGoogle Scholar
- Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, O'Hara B, Rossiter S, Anthony S, Madhani M, Selwood D, et al: Disruption of methylarginine metabolism impairs vascular homeostasis. Nat Med. 2007, 13 (2): 198-203. 10.1038/nm1543.View ArticlePubMedGoogle Scholar
- Hasegawa K, Wakino S, Tatematsu S, Yoshioka K, Homma K, Sugano N, Kimoto M, Hayashi K, Itoh H: Role of asymmetric dimethylarginine in vascular injury in transgenic mice overexpressing dimethylarginie dimethylaminohydrolase 2. Circ Res. 2007, 101 (2): e2-10. 10.1161/CIRCRESAHA.107.156901.View ArticlePubMedGoogle Scholar
- Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King TE, Flaherty KR, Schwartz DA, Noble PW, Raghu G, et al: The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005, 142 (12 Pt 1): 963-967.View ArticlePubMedGoogle Scholar
- Selman M, Thannickal VJ, Pardo A, Zisman DA, Martinez FJ, Lynch JP: Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs. 2004, 64 (4): 405-430. 10.2165/00003495-200464040-00005.View ArticlePubMedGoogle Scholar
- Li X, Rayford H, Uhal BD: Essential roles for angiotensin receptor AT1a in bleomycin-induced apoptosis and lung fibrosis in mice. Am J Pathol. 2003, 163 (6): 2523-2530.View ArticlePubMedPubMed CentralGoogle Scholar
- Konigshoff M, Wilhelm A, Jahn A, Sedding D, Amarie OV, Eul B, Seeger W, Fink L, Gunther A, Eickelberg O, et al: The angiotensin II receptor 2 is expressed and mediates angiotensin II signaling in lung fibrosis. Am J Respir Cell Mol Biol. 2007, 37 (6): 640-650. 10.1165/rcmb.2006-0379TR.View ArticlePubMedGoogle Scholar
- Jacobi J, Maas R, Cordasic N, Koch K, Schmieder RE, Boger RH, Hilgers KF: Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice. Am J Physiol Heart Circ Physiol. 2008, 294 (2): H1058-1066. 10.1152/ajpheart.01103.2007.View ArticlePubMedGoogle Scholar
- Wells SM, Buford MC, Migliaccio CT, Holian A: Elevated Asymmetric Dimethylarginine Alters Lung Function and Induces Collagen Deposition in Mice. Am J Respir Cell Mol Biol. 2008,Google Scholar
- Kitowska K, Zakrzewicz D, Konigshoff M, Chrobak I, Grimminger F, Seeger W, Bulau P, Eickelberg O: Functional role and species-specific contribution of arginases in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2008, 294 (1): L34-45. 10.1152/ajplung.00007.2007.View ArticlePubMedGoogle Scholar
- Richir MC, van Leeuwen PA, Berg van den A, Wessels R, Twisk JW, Rauwerda JA, Teerlink T, de Vries TP, van Elburg RM: Plasma ADMA concentrations at birth and mechanical ventilation in preterm infants: a prospective pilot study. Ped Pulmonol. 2008, 43 (12): 1161-1166. 10.1002/ppul.20886.View ArticleGoogle Scholar
- Ricciardolo FL, Nijkamp FP, Folkerts G: Nitric oxide synthase (NOS) as therapeutic target for asthma and chronic obstructive pulmonary disease. Curr Drug Targets. 2006, 7 (6): 721-735. 10.2174/138945006777435290.View ArticlePubMedGoogle Scholar
- Corradi M, Montuschi P, Donnelly LE, Pesci A, Kharitonov SA, Barnes PJ: Increased nitrosothiols in exhaled breath condensate in inflammatory airway diseases. Am J Respir Crit Care Med. 2001, 163 (4): 854-858.View ArticlePubMedGoogle Scholar
- Eid HM, Arnesen H, Hjerkinn EM, Lyberg T, Seljeflot I: Relationship between obesity, smoking, and the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine. Metabolism. 2004, 53 (12): 1574-1579. 10.1016/j.metabol.2004.06.026.View ArticlePubMedGoogle Scholar
- Maas R, Schulze F, Baumert J, Lowel H, Hamraz K, Schwedhelm E, Koenig W, Boger RH: Asymmetric dimethylarginine, smoking, and risk of coronary heart disease in apparently healthy men: prospective analysis from the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung in der Region Augsburg study and experimental data. Clin Chem. 2007, 53 (4): 693-701. 10.1373/clinchem.2006.081893.View ArticlePubMedGoogle Scholar
- Wang J, Sim AS, Wang XL, Salonikas C, Naidoo D, Wilcken DE: Relations between plasma asymmetric dimethylarginine (ADMA) and risk factors for coronary disease. Atherosclerosis. 2006, 184 (2): 383-388. 10.1016/j.atherosclerosis.2005.05.002.View ArticlePubMedGoogle Scholar
- Zhang WZ, Venardos K, Chin-Dusting J, Kaye DM: Adverse effects of cigarette smoke on NO bioavailability: role of arginine metabolism and oxidative stress. Hypertension. 2006, 48 (2): 278-285. 10.1161/01.HYP.0000231509.27406.42.View ArticlePubMedGoogle Scholar
- Cardounel AJ, Cui H, Samouilov A, Johnson W, Kearns P, Tsai AL, Berka V, Zweier JL: Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function. J Biol Chem. 2007, 282 (2): 879-887. 10.1074/jbc.M603606200.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/9/5/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.