Next Article in Journal
Anti-Inflammatory and Analgesic Activities of a Novel Biflavonoid from Shells of Camellia oleifera
Next Article in Special Issue
Roles of Nitric Oxide and Asymmetric Dimethylarginine in Pregnancy and Fetal Programming
Previous Article in Journal
Proposal of a New Method for Measuring Förster Resonance Energy Transfer (FRET) Rapidly, Quantitatively and Non-Destructively
Previous Article in Special Issue
Asymmetric Dimethylarginine as a Surrogate Marker of Endothelial Dysfunction and Cardiovascular Risk in Patients with Systemic Rheumatic Diseases
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Protein Arginine Methyltransferases (PRMTs): Promising Targets for the Treatment of Pulmonary Disorders

Dariusz Zakrzewicz
Anna Zakrzewicz
Klaus T. Preissner
Philipp Markart
4 and
Malgorzata Wygrecka
Department of Biochemistry, Faculty of Medicine, University of Giessen Lung Center, Friedrichstrasse 24, 35392 Giessen, Germany
Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus Liebig-University Giessen, Rudolf-Buchheim-Str. 7, D-35385 Giessen, Germany
Department of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research, Giessen, Germany
Department of Internal Medicine, Faculty of Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research, Giessen, Germany
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2012, 13(10), 12383-12400;
Submission received: 3 September 2012 / Revised: 19 September 2012 / Accepted: 19 September 2012 / Published: 27 September 2012
(This article belongs to the Special Issue ADMA and Nitrergic System)


Protein arginine methylation is a novel posttranslational modification that plays a pivotal role in a variety of intracellular events, such as signal transduction, protein-protein interaction and transcriptional regulation, either by the direct regulation of protein function or by metabolic products originating from protein arginine methylation that influence nitric oxide (NO)-dependent processes. A growing body of evidence suggests that both mechanisms are implicated in cardiovascular and pulmonary diseases. This review will present and discuss recent research on PRMTs and the methylation of non-histone proteins and its consequences for the pathogenesis of various lung disorders, including lung cancer, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease and asthma. This article will also highlight novel directions for possible future investigations to evaluate the functional contribution of arginine methylation in lung homeostasis and disease.

1. Introduction

Pulmonary diseases (PD), including lung cancer, idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH), chronic obstructive pulmonary disease (COPD) and asthma are the second leading cause of death worldwide. Their rate of incidence is on the increase and PD are usually associated with a high socio-economic burden [1,2]. Despite substantial progress in understanding the epidemiology and pathophysiology, we still lack efficient pharmacological therapeutic options for many PD, particularly in regard to improving mortality rates. As lung transplantation is an option for only a limited number of patients with end-stage disease [36], there is an urgent need to identify novel, more effective therapies for PD.
Post-translational modifications of proteins play an important role in signal transduction allowing cells to respond to changes and events occurring in extracellular milieu. Although the role of acetylation and phosphorylation has already been extensively discussed in the context of PD [710], the importance of other types of protein modifications, including ubiquitination and methylation has now begun to be recognized [11,12]. Protein arginine methylation represents a novel protein modification that has been implicated in a number of cellular processes including transduction of intracellular signaling [13], DNA repair [1416], RNA processing [17,18], protein-protein interaction and regulation of gene expression [19,20], thereby controlling cell differentiation, proliferation, migration and apoptosis [21,22]. Thus, any alteration of intracellular protein methylation may disturb cellular homeostasis and consequently lead to various, uncontrolled, pathological events observed in PD.

2. Protein Arginine Methylation

Protein arginine methylation was initially discovered in the calf thymus over 40 years ago by W. K. Paik [23]. Since then, arginine methylation has been extensively studied, demonstrating its great importance in the regulation of protein functions in a variety of fundamental cellular processes. The methylation of protein arginine residues is catalyzed by a family of intracellular enzymes termed protein arginine methyltransferases (PRMT) [11,24]. They catalyze the addition of one or two methyl groups to the guanidino nitrogen atoms of arginine resulting in either ω-NG-monomethylarginine (MMA), ω-NG, NG-asymmetric (ADMA) or ω-NG, N′G-symmetric dimethylarginine (SDMA). In humans, PRMTs have been classified into type I and type II, depending on their specific catalytic activities. Both types of enzymes first catalyze the formation of MMA as an intermediate. In a second step, type I enzymes (PRMT1 [25], PRMT3 [26], CARM1/PRMT4 [19], PRMT6 [27] and PRMT8 [28,29]) lead to the formation of ADMA, whereas the type II enzymes (PRMT5 [30,31] and PRMT7 [32,33]) produce SDMA (Figure 1). Of note is that PRMT2 was previously classified into type I enzymes [34] but its methyltransferase activity has just recently been characterized in vitro [35]. After breakdown of mono- and dimethylated intracellular proteins, free MMA, ADMA and SDMA can be released into cells.
Thus, methylation of arginine residues within proteins by PRMTs and the subsequent proteolysis of these arginine-methylated proteins by proteasome and autophagy pathways represent the major source of free intracellular methylarginine [3638], since there is currently no evidence that free L-arginine (L-Arg) can be methylated [39].
Free cellular MMA and ADMA, but not SDMA, can be intracellularly degraded to citrulline and mono- or dimethylamines, respectively, by two dimethylarginine dimethylaminohydrolases (DDAH): DDAH1 and DDAH2 [11,36]. Alternatively, ADMA can be converted to α-keto valeric acid by alanine:glyoxylate aminotransferase 2 [40], and SDMA may be catabolized in vivo when injected intraperitonelly into rats, although the enzymes involved have not been identified thus far [41].

3. Protein Arginine Methyltransferases in Pulmonary Disorders

3.1. Lung Cancer

Lung cancer is the leading cause of cancer-related death worldwide. The prognosis of lung cancer is poor due to the fact that this disease can be symptomless in the early stage; therefore, most lung carcinomas are diagnosed at an advanced stage when distant metastases are already present. Current standard therapies include surgical resection, platinum-based doublet chemotherapy and radiation therapy alone or in combination. However, these therapies rarely cure the disease and the overall 5-year survival rate is still only 5%–15% [4244]. Therefore, searching for new therapeutic agents and exploring novel intervention targets might provide more clinical benefits and indicate better outcomes in lung cancer therapy.
Based on histologic appearance and presumed cellular origin, lung cancer can be divided into two main classes. Small cell lung cancer (SCLC) is of neuroendocrine origin, while non-small cell lung cancer (NSCLC) is predominantly epithelial. NSCLC, which accounts for approximately 75% of all lung cancers, is divided further into adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma histologies [44].
A growing body of evidence suggests that PRMTs are involved in human carcinogenesis, including lung cancer. Similarly to previously published studies on breast, colon and bladder cancers [45,46], elevated PRMT1 and PRMT6 expression has recently been found in various types of lung cancer including SCLC and NSCLC [47]. As PRMT1 is a major type I PRMT, it is not surprising that its enhanced expression is mirrored by increased ADMA content in systemic circulation in lung cancer patients as compared to nontumor control subjects [47]. ADMA may control pulmonary cell behavior either via direct effects on gene expression and protein function [48] or via inhibition of nitric oxide synthase (NOS), which consequently leads to alterations in NO generation [49]. Overall, the role of ADMA in lung cancer biology remains elusive and further studies are needed to fully decipher the mechanism of its action in these pathological conditions.
In contrast, contribution of PRMTs to the pathogenesis of lung cancer is well recognized and confirmed in numerous in vitro studies. siRNA-mediated knockdown of PRMT1 and PRMT6 was found to lead to suppression of lung cancer cell growth, most probably by influencing G1-S transition in the cell cycle. Importantly, expression profile analysis of PRMT1 and PRMT6-depleted cells indicated that PRMT1 and PRMT6 operate within many cellular pathways, supporting their regulatory role in the cell cycle, RNA processing and chromatin modification, processes fundamentally important for cancer cell proliferation [47]. This is in line with previous studies using PRMT1-deficient mice, which demonstrated that the loss of PRMT1 in embryonic fibroblasts (MEFs) leads to spontaneous DNA damage, delay in cell cycle progression, and reduction of the cell growth [22]. Similarly to PRMT1, knockdown of PRMT6 inhibited estrogen-stimulated proliferation of breast cancer cells [50] and impaired cell migration and invasion of U2OS cells [51]. Moreover, reduced PRMT6 expression was associated with better overall relapse-free and distant metastasis-free survival in breast cancer patients with the estrogen receptor (ER (ESR1))-positive invasive ductile carcinoma, supporting the notion that PRMT6-dependent transcription and alternative splicing may also be involved in lung cancer pathophysiology [52].
There is no direct evidence for dysregulation of other PRMTs, such as PRMT2, PRMT4 and PRMT5 in lung tumorigenesis, although these molecules participate in the pathogenesis of other types of human cancer. For instance, PRMT2 and its splice variants were found to play a role in the progression of breast cancer by modulation of promoter activities of the ERα-targeted genes thereby controlling cancer cell proliferation [53].
PRMT4 overexpression has been demonstrated in grade-III breast cancers and prostate adenocarcinomas [5457]. In human breast and prostate cancer cells, CARM1/PRMT4 knockdown resulted in the inhibition of cell proliferation and cell cycle progression and in the enhancement of cell apoptosis [55,56]. In colorectal cancer cells, CARM1/PRMT4 was reported to be an important positive regulator of Wnt/β-catenin-dependent signaling [58], a developmentally active pathway, well investigated in lung cancer biology [59,60]. This all indicates that increased PRMT4 expression may lead to pathological changes observed in tumorigenesis. However, in contrast to those studies, O’Brien et al. suggested that PRMT4 is required for proper differentiation of alveolar cells and that overexpression of PRMT4 rather inhibits than potentiates pulmonary epithelial cell proliferation during lung development [61]. This opposite effect of PRMT4 overexpression on lung alveolar cell growth might be explained by distinct gene expression profiles and by the presence or absence of different PRMT4 protein targets in alveolar versus cancer cells. Additionally, it has to be kept in mind that as PRMT4 is highly expressed in the lung tissue as compared to other organs, this suggests an important role of this molecule in maintenance of lung homeostasis [62,63]. Thus, abundant pulmonary PRMT4 expression together with its ability to control cell proliferation makes PRMT4 a potential target for further investigations on lung cancer development and progression.
Uncontrolled cell growth in human tissues is regulated by another member of the PRMT family, PRMT5. It is a molecule that may control proliferation of cancer cells by a mechanism involving HIF-1α activation or direct methylation of E2F-1 transcription factor [64,65]. In addition, PRMT5 is highly expressed in human breast cancer [66]. Coexpression of PRMT5 with programmed cell death 4 (PDCD4) influences tumor suppressor properties of PDCD4 resulting in accelerated tumor growth in a murine orthotopic model of breast cancer. In breast cancer patients whose tumors contain high level of PRMT5, elevated PDCD4 expression correlates with a worse outcome [66]. PRMT5 has also been implicated in tumorigenesis by its interaction with p53 protein [67], the most frequently inactivated gene in human cancers [68]. p53 can regulate apoptosis, cell cycle arrest and senescence, and re-activation of p53 may be a plausible target for cancer therapy [6871]. It has recently been reported that DNA damage induces PRMT5-dependent p53 arginine methylation, an event that changes the biochemical properties and functional outcome of the p53 response. This response involves the activation of target genes, such as cyclin dependent kinase inhibitor p21, NOXA, APAF1 and PUMA, which are important in regulating p53-dependent growth arrest [71]. Hence, PRMT5 depletion in human osteosarcoma U2OS cells was found to induce p53-dependent apoptosis [67]. Thus, regulation of arginine metylation status in p53 may provide new therapeutical options for the treatment of various types of lung cancer [72].
Collectively, the findings mentioned above provide evidence that links dysregulated protein arginine methylation and aberrant PRMT expression/activity with oncogenic events observed during lung cancer development and progression. In addition, current results indicate that PRMT1 and PRMT6 are involved in lung tumorigenesis. However, further studies are needed to fully decipher the molecular mechanisms of their action.

3.2. Pulmonary Fibrosis

In contrast to the well-established role of PRMTs in cancer cell biology, studies of protein arginine methylation in IPF are limited. Accumulating evidence suggests however, that arginine methylation may be involved in the progression of IPF, a chronic, irreversible and fatal lung disease of unknown etiology [6,73]. The main features of IPF are alveolar cell apoptosis, proliferation of lung fibroblasts/myofibroblasts and extracellular matrix protein deposition in the lung interstitium [6,74]. The hallmark lesions of IPF are fibroblast foci occurring in subepithelial layers adjacent to areas of alveolar epithelial cell injury. Subepithelial localization of fibroblast foci strongly suggests that altered epithelial-mesenchymal crosstalk contributes to the pathobiology of IPF [6,74]. It is assumed that repetitive alveolar epithelial cell injury and subsequent aberrant repair lead to excessive growth factor activation and fibrotic transformation [6,73,74]. Multiple cytokines and growth factors, such as transforming growth factor (TGF)-β1, interleukin (IL) -4, -13, -21 [75] and angiotensin II (ANGII) [76,77] have been identified as potent regulators of fibrotic processes, directly or indirectly, for example, by regulation of the expression of coagulation factors which in turn contributes to the development of IPF [7880].
The role of ANGII is well established in the pathogenesis of IPF. It was demonstrated that fibroblasts isolated from IPF lungs produce more ANGII as compared to fibroblasts isolated from donor lungs [81]. ANGII was found to induce apoptosis of epithelial and endothelial cells within lung tissue via ANGII receptor subtype AT(1) [82,83]. In addition, ANG II and aldosterone, a hormone regulated by the renin-angiotensin system, may significantly enhance the proliferation of various cells [8486], suggesting that use of ANGII-receptor antagonists and aldosterone-receptor inhibitors may prevent fibrosis. Indeed, it was shown that a blockade of ANGII signaling attenuates the development of pulmonary and renal fibrosis [76,77,87], and, in contrast, administration of ANGII into the mouse potentiates perivascular and interstitial renal fibrosis, most likely via aggravation of PRMT1, which did not, however, alter ADMA levels in blood circulation [88]. This no net effect of ANGII treatment on systemic ADMA content could be explained by concomitant up-regulation of ADMA-generating (PRMT1) and ADMA-degrading (DDAH2) enzymes [88]. In vitro studies revealed that ANGII may induce PRMT1 expression and endothelial cell activation, resulting in the generation of reactive oxygen species (ROS) [89], key players in the establishment/progression of pulmonary fibrosis in animal models and possibly in human IPF [90,91]. Enhanced PRMT1 expression may also affect the regulation of transcription as PRMT1 was found to co-activate the nuclear factor-κB (NF-κB) signaling pathway [92] that, under stimulatory conditions, may trigger expression of MMP1 [93], MMP2 [94], MMP9 [93,95], collagen I [96], all proteins that have been reported to be up-regulated in the lungs of IPF patients and animal models of pulmonary fibrosis [6]. In addition, PRMT1 may induce structural changes in the target proteins, and thus influence the activation and differentiation of a variety of cells [21,97]. As renal and pulmonary fibrosis share similar features including fibrotic cytokines (ANGII, TGF-β) and ROS overproduction, and activated myofibroblasts originating from local mesenchymal cells, it can be speculated that enhanced PRMT1 expression may participate in the development of lung fibrosis by various mechanisms which may not necessarily have to be ADMA-dependent.
To date, there is only one report suggesting dysregulation of PRMT expression during lung fibrosis development. In this article, the authors examined the L-Arg metabolism in pulmonary fibrosis using a bleomycin-induced lung injury model [98]. In this model, fibrosis develops as a consequence of an overwhelming inflammatory response [99,100]. RNA and protein expression analysis of lung tissue of bleomycin-treated mice revealed dysregulation of expression of only one PRMT isoform, namely PRMT6. The PRMT6 level was found to be reduced during the inflammatory phase, but recovered afterwards, and it was upregulated in the fibrotic stage [98]. Unfortunately, the underlying molecular mechanism responsible for dysregulated PRMT6 expression in mouse fibrotic lungs was not investigated in this study. How PRMT6 may contribute to the development of pulmonary fibrosis can currently only be speculated, however, it has previously been reported that PRMT6 may regulate expression of genes, either by modulation of histone 3 function or by interaction with specific gene promoter regions [51,101]. One of the transcriptional targets of PRMT6 is thrombospondin-1 (TSP-1), a molecule critical for normal lung homeostasis [102]. Taking into consideration that TSP-1 is a major activator of TGF-β1 [103], a cytokine involved in the pathogenesis of pulmonary fibrosis [74,99], it is conceivable that altered PRMT6 expression might be an important factor in regulating the fibrotic processes. However, the mechanistic insights of PRMT action and causal relationship between fibrogenesis and PRMT expression and activity remain to be determined in future studies.

3.3. Pulmonary Hypertension

Pulmonary Hypertension (PH) is a hemodynamic and pathophysiological state defined by an increase in mean pulmonary artery pressure ≥25 mmHg. The current clinical classification comprises six clinical groups including pulmonary arterial hypertension (PAH; idiopathic; heritable; drug-induced; or associated with other disease conditions), PH due to left heart failure, due to lung diseases and/or hypoxia, and chronic thrombembolic PH (CTEPH). The pathophysiology of PH includes endothelial dysfunction and pulmonary arterial smooth muscle cell (PASMC) hypertrophy and proliferation, leading to the occlusion of pulmonary arterioles [104107]. The mechanisms of endothelial vasodilator dysfunction in PH are multifactorial involving multiple pathways and mediators. One of them is NO, a well-known vasodilator that essentially controls a diverse range of pulmonary functions, such as macrophage activity, pulmonary artery vasodilation, or bronchoconstriction [108]. A product of protein arginine methylation, ADMA, is a naturally occurring nitric oxide synthase (NOS) inhibitor [49]. Elevated ADMA concentrations have been detected in the plasma of patients with idiopathic (i) PAH [109111], CTEPH [112], PAH-related sickle cell disease [113] and systemic sclerosis [114], suggesting a strong association of circulating dimethylarginine levels with PH pathogenesis. It remains unclear which DDAH or PRMT isoforms control ADMA tissue and plasma levels under those pathological conditions. While some groups have reported decreased DDAH1 expression along with increased ADMA levels [115,116], others have detected decreased DDAH2 in the same conditions [110,117]. PRMT2 protein expression was found to be upregulated in mice exposed to chronic hypoxia, resulting in increased ADMA levels, thereby supporting an important role of PRMT-mediated ADMA generation in hypoxia-induced PH [34]. Comprehensive analysis of methylarginine content in the lungs of patients with PAH demonstrated significantly lower levels of protein-incorporated ADMA in the PAH lung tissue samples as compared to controls [118]. This was most likely a consequence of decreased expression of PRMT1 and asymmetrically dimethylated proteins. Moreover, in vitro and ex vivo studies have revealed that decreased PRMT1 expression directly leads to reduced cellular methylation and increased PASMC proliferation, which in turn might initiate, perpetuate, or potentate the vascular remodeling process in pulmonary arterioles in PAH [118].

3.4. Chronic Obstructive Pulmonary Disease and Asthma

Asthma is a chronic inflammatory disorder of the airways characterized by variable and usually reversible airflow obstruction. Asthma often has its first manifestation in childhood and may be classified as allergic (extrinsic) or non-allergic (intrinsic). In contrast, Chronic Obstructive Pulmonary Disease (COPD) is usually related to tobacco smoking and develops in mid to later life and is characterized by incomplete reversible airflow limitation resulting in a progressive decline in lung function leading to premature death. In both diseases inflammation plays an important role [119121]. In asthma, airway inflammation is a multicellular process principally involving antigen presenting cells, eosinophils, mast cells and TH2 lymphocytes [121]. It was previously reported that activation of T lymphocytes is controlled by protein arginine methylation [13,122]. In this regard, methylation of the nuclear factor of activated T-cells (NFAT) interacting protein 45 (NIP45) by PRMT1 increases the activity of NFAT, which is required for the production of cytokines by T lymphocytes [123]. Similarly, PRMT1-dependent methylation of STAT proteins potentiates cytokine expression in various cells and thus impacts on many intracellular signaling pathways [124]. These findings suggest that targeting protein arginine methylation is a feasible strategy for modulation of the T lymphocyte function, offering a novel therapeutical option for the treatment of T cell-mediated disorders, such as autoimmune disease, transplant rejection, but also potentially COPD and asthma [13,122,125].
Enhanced ADMA levels have been demonstrated in allergically inflamed mouse lungs, as well as in lung and sputum samples of asthma patients [126,127]. In line with these findings exogenous administration of ADMA potentiated lung inflammation in a murine model of allergic asthma [128]. The altered ADMA metabolism in the previously mentioned pathological conditions might be a consequence of enhanced type I PRMT expression or activity. Indeed, increased expression of PRMT2 has been demonstrated in a murine model of lung allergic airway inflammation [126] and elevated levels of PRMT1, PRMT2, PRMT3 (but not PRMT4) were found in the lungs of a rat model of Ag-induced pulmonary inflammation (AIPI) [129]. In AIPI rats, epithelial IL-4-triggered PRMT1 expression enhanced eotaxin-1 and CCR3 receptor expression thus promoting recruitment of eosinophils to the lung. Administration of AMI-1, specific inhibitor of PRMT activity, to AIPI rats ameliorated pulmonary inflammation, reduced humoral immune response and abrogated eosinophil infiltration suggesting a pivotal role of PRMT, particularly PRMT1, in asthma pathogenesis [129].
As cigarette smoke represents the main risk factor for COPD, several studies have investigated the relationship between cigarette smoking and ADMA levels. While some studies have found decreased ADMA levels in smokers as compared to non-smokers, others have detected increased amounts of ADMA in cigarette smoking subjects [130,131]. Despite conflicting results on arginine metabolism in COPD patients, altered ADMA levels in smokers might be associated with dysregulated PRMT activities and the ubiquitin-proteasome system, an ATP-dependent proteolytic pathway, which has been implicated in the ADMA metabolism [36,37].
In summary, since limited data on protein arginine methylation in COPD and asthma exists, further in vitro and in vivo studies are needed to decipher the relationship between dysregulated PRMT expression and/or activity and pathogenesis of the aforementioned diseases.

4. Conclusions

In conclusion, dysregulated protein arginine methylation and abnormal expression of PRMTs have recently been shown to contribute to the pathogenesis of PD in experimental animal models as well as in humans (Figure 2). However, it is still not clear how and to what extent PRMT-dependent posttranslational modification of proteins may influence protein functions and how dimethylarginines can regulate biological processes. It seems that PRMT dependent alterations of cellular activities might be the cause or the result of pathological changes observed in discussed PD. Therefore, future studies are required to answer the question as to whether PRMTs may offer a new potential therapeutical option for the treatment of PD.


Supported by the start-up grant from the Excellence Cluster “Cardiopulmonary System” (ECCPS) (Dariusz Zakrzewicz) and SFB/TR84 (Klaus T. Preissner and Malgorzata Wygrecka).
  • Conflict of InterestThe authors declare no conflict of interest.


  1. Heron, M.; Hoyert, D.L.; Murphy, S.L.; Xu, J.; Kochanek, K.D.; Tejada-Vera, B. Deaths: Final data for 2006. Natl. Vital Stat. Rep 2009, 57, 1–134. [Google Scholar]
  2. Yach, D.; Hawkes, C.; Gould, C.L.; Hofman, K.J. The global burden of chronic diseases: Overcoming impediments to prevention and control. JAMA J. Am. Med. Assoc 2004, 291, 2616–2622. [Google Scholar]
  3. Orens, J.B.; Shearon, T.H.; Freudenberger, R.S.; Conte, J.V.; Bhorade, S.M.; Ardehali, A. Thoracic organ transplantation in the United States, 1995–2004. Am. J. Transplant 2006, 6, 1188–1197. [Google Scholar]
  4. Trulock, E.P.; Christie, J.D.; Edwards, L.B.; Boucek, M.M.; Aurora, P.; Taylor, D.O.; Dobbels, F.; Rahmel, A.O.; Keck, B.M.; Hertz, M.I. Registry of the international society for heart and lung transplantation: Twenty-fourth official adult lung and heart-lung transplantation report—2007. J. Heart Lung Transplant 2007, 26, 782–795. [Google Scholar]
  5. O’Beirne, S.; Counihan, I.P.; Keane, M.P. Interstitial lung disease and lung transplantation. Semin. Respir. Crit. Care Med 2010, 31, 139–146. [Google Scholar]
  6. King, T.E., Jr; Pardo, A.; Selman, M. Idiopathic pulmonary fibrosis. Lancet 2011, 378, 1949–1961. [Google Scholar]
  7. Barnes, P.J. Targeting the epigenome in the treatment of asthma and chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc 2009, 6, 693–696. [Google Scholar]
  8. Oka, M.; Fagan, K.A.; Jones, P.L.; McMurtry, I.F. Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension. Br. J. Pharmacol 2008, 155, 444–454. [Google Scholar]
  9. Barlesi, F.; Giaccone, G.; Gallegos-Ruiz, M.I.; Loundou, A.; Span, S.W.; Lefesvre, P.; Kruyt, F.A.; Rodriguez, J.A. Global histone modifications predict prognosis of resected non small-cell lung cancer. J. Clin. Oncol 2007, 25, 4358–4364. [Google Scholar]
  10. Adcock, I.M.; Ito, K.; Barnes, P.J. Histone deacetylation: An important mechanism in inflammatory lung diseases. COPD Int. J. Chronic. Obstruct. Pulm. Dis 2005, 2, 445–455. [Google Scholar]
  11. Zakrzewicz, D.; Eickelberg, O. From arginine methylation to ADMA: A novel mechanism with therapeutic potential in chronic lung diseases. BMC Pulm. Med 2009, 9, 5. [Google Scholar]
  12. Debigare, R.; Cote, C.H.; Maltais, F. Ubiquitination and proteolysis in limb and respiratory muscles of patients with chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc 2010, 7, 84–90. [Google Scholar]
  13. Blanchet, F.; Schurter, B.T.; Acuto, O. Protein arginine methylation in lymphocyte signaling. Curr. Opin. Immunol 2006, 18, 321–328. [Google Scholar]
  14. Lake, A.N.; Bedford, M.T. Protein methylation and DNA repair. Mutat. Res 2007, 618, 91–101. [Google Scholar]
  15. El-Andaloussi, N.; Valovka, T.; Toueille, M.; Hassa, P.O.; Gehrig, P.; Covic, M.; Hubscher, U.; Hottiger, M.O. Methylation of DNA polymerase beta by protein arginine methyltransferase 1 regulates its binding to proliferating cell nuclear antigen. FASEB J 2007, 21, 26–34. [Google Scholar]
  16. El-Andaloussi, N.; Valovka, T.; Toueille, M.; Steinacher, R.; Focke, F.; Gehrig, P.; Covic, M.; Hassa, P.O.; Schar, P.; Hubscher, U.; et al. Arginine methylation regulates DNA polymerase beta. Mol. Cell 2006, 22, 51–62. [Google Scholar]
  17. Cheng, D.; Cote, J.; Shaaban, S.; Bedford, M.T. The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing. Mol. Cell 2007, 25, 71–83. [Google Scholar]
  18. Boisvert, F.M.; Cote, J.; Boulanger, M.C.; Cleroux, P.; Bachand, F.; Autexier, C.; Richard, S. Symmetrical dimethylarginine methylation is required for the localization of SMN in Cajal bodies and pre-mRNA splicing. J. Cell Biol 2002, 159, 957–969. [Google Scholar]
  19. Chen, D.; Ma, H.; Hong, H.; Koh, S.S.; Huang, S.M.; Schurter, B.T.; Aswad, D.W.; Stallcup, M.R. Regulation of transcription by a protein methyltransferase. Science 1999, 284, 2174–2177. [Google Scholar]
  20. Iberg, A.N.; Espejo, A.; Cheng, D.; Kim, D.; Michaud-Levesque, J.; Richard, S.; Bedford, M.T. Arginine methylation of the histone H3 tail impedes effector binding. J. Biol. Chem 2008, 283, 3006–3010. [Google Scholar]
  21. Infantino, S.; Benz, B.; Waldmann, T.; Jung, M.; Schneider, R.; Reth, M. Arginine methylation of the B cell antigen receptor promotes differentiation. J. Exp. Med 2010, 207, 711–719. [Google Scholar]
  22. Yu, Z.; Chen, T.; Hebert, J.; Li, E.; Richard, S. A mouse PRMT1 null allele defines an essential role for arginine methylation in genome maintenance and cell proliferation. Mol. Cell Biol 2009, 29, 2982–2996. [Google Scholar]
  23. Paik, W.K.; Kim, S. Enzymatic methylation of protein fractions from calf thymus nuclei. Biochem. Biophys. Res. Commun 1967, 29, 14–20. [Google Scholar]
  24. Bedford, M.T.; Clarke, S.G. Protein arginine methylation in mammals: Who, what, and why. Mol. Cell 2009, 33, 1–13. [Google Scholar]
  25. Lin, W.J.; Gary, J.D.; Yang, M.C.; Clarke, S.; Herschman, H.R. The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase. J. Biol. Chem 1996, 271, 15034–15044. [Google Scholar]
  26. Tang, J.; Gary, J.D.; Clarke, S.; Herschman, H.R. PRMT 3, a type I protein arginine N-methyltransferase that differs from PRMT1 in its oligomerization, subcellular localization, substrate specificity, and regulation. J. Biol. Chem 1998, 273, 16935–16945. [Google Scholar]
  27. Frankel, A.; Yadav, N.; Lee, J.; Branscombe, T.L.; Clarke, S.; Bedford, M.T. The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity. J. Biol. Chem 2002, 277, 3537–3543. [Google Scholar]
  28. Lee, J.; Sayegh, J.; Daniel, J.; Clarke, S.; Bedford, M.T. PRMT8, a new membrane-bound tissue-specific member of the protein arginine methyltransferase family. J. Biol. Chem 2005, 280, 32890–32896. [Google Scholar]
  29. Sayegh, J.; Webb, K.; Cheng, D.; Bedford, M.T.; Clarke, S.G. Regulation of protein arginine methyltransferase 8 (PRMT8) activity by its N-terminal domain. J. Biol. Chem 2007, 282, 36444–36453. [Google Scholar]
  30. Branscombe, T.L.; Frankel, A.; Lee, J.H.; Cook, J.R.; Yang, Z.; Pestka, S.; Clarke, S. PRMT5 (Janus kinase-binding protein 1) catalyzes the formation of symmetric dimethylarginine residues in proteins. J. Biol. Chem 2001, 276, 32971–32976. [Google Scholar]
  31. Pollack, B.P.; Kotenko, S.V.; He, W.; Izotova, L.S.; Barnoski, B.L.; Pestka, S. The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity. J. Biol. Chem 1999, 274, 31531–31542. [Google Scholar]
  32. Lee, J.H.; Cook, J.R.; Yang, Z.H.; Mirochnitchenko, O.; Gunderson, S.I.; Felix, A.M.; Herth, N.; Hoffmann, R.; Pestka, S. PRMT7, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine. J. Biol. Chem 2005, 280, 3656–3664. [Google Scholar]
  33. Miranda, T.B.; Miranda, M.; Frankel, A.; Clarke, S. PRMT7 is a member of the protein arginine methyltransferase family with a distinct substrate specificity. J. Biol. Chem 2004, 279, 22902–22907. [Google Scholar]
  34. Yildirim, A.O.; Bulau, P.; Zakrzewicz, D.; Kitowska, K.E.; Weissmann, N.; Grimminger, F.; Morty, R.E.; Eickelberg, O. Increased protein arginine methylation in chronic hypoxia: Role of protein arginine methyltransferases. Am. J. Respir. Cell Mol. Biol 2006, 35, 436–443. [Google Scholar]
  35. Lakowski, T.M.; Frankel, A. Kinetic analysis of human protein arginine N-methyltransferase 2: Formation of monomethyl- and asymmetric dimethyl-arginine residues on histone H4. Biochem. J 2009, 421, 253–261. [Google Scholar]
  36. Teerlink, T. ADMA metabolism and clearance. Vasc. Med 2005, 10, S73–S81. [Google Scholar]
  37. Shirakawa, T.; Kako, K.; Shimada, T.; Nagashima, Y.; Nakamura, A.; Ishida, J.; Fukamizu, A. Production of free methylarginines via the proteasome and autophagy pathways in cultured cells. Mol. Med. Report 2011, 4, 615–620. [Google Scholar]
  38. Bulau, P.; Zakrzewicz, D.; Kitowska, K.; Wardega, B.; Kreuder, J.; Eickelberg, O. Quantitative assessment of arginine methylation in free versus protein-incorporated amino acids in vitro and in vivo using protein hydrolysis and high-performance liquid chromatography. Biotechniques 2006, 40, 305–310. [Google Scholar]
  39. Vallance, P.; Leiper, J. Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler. Thromb. Vasc. Biol 2004, 24, 1023–1030. [Google Scholar]
  40. 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, 20938–20945. [Google Scholar]
  41. Ogawa, T.; Kimoto, M.; Watanabe, H.; Sasaoka, K. Metabolism of NG,NG-and NG,N′G-dimethylarginine in rats. Arch. Biochem. Biophys 1987, 252, 526–537. [Google Scholar]
  42. Jemal, A.; Siegel, R.; Ward, E.; Hao, Y.; Xu, J.; Thun, M.J. Cancer statistics, 2009. CA Cancer J. Clin 2009, 59, 225–249. [Google Scholar]
  43. Ramalingam, S.S.; Owonikoko, T.K.; Khuri, F.R. Lung cancer: New biological insights and recent therapeutic advances. CA Cancer J. Clin 2011, 61, 91–112. [Google Scholar]
  44. Risch, A.; Plass, C. Lung cancer epigenetics and genetics. Int. J. Cancer 2008, 123, 1–7. [Google Scholar]
  45. Goulet, I.; Gauvin, G.; Boisvenue, S.; Cote, J. Alternative splicing yields protein arginine methyltransferase 1 isoforms with distinct activity, substrate specificity, and subcellular localization. J. Biol. Chem 2007, 282, 33009–33021. [Google Scholar]
  46. Mathioudaki, K.; Papadokostopoulou, A.; Scorilas, A.; Xynopoulos, D.; Agnanti, N.; Talieri, M. The PRMT1 gene expression pattern in colon cancer. Br. J. Cancer 2008, 99, 2094–2099. [Google Scholar]
  47. Yoshimatsu, M.; Toyokawa, G.; Hayami, S.; Unoki, M.; Tsunoda, T.; Field, H.I.; Kelly, J.D.; Neal, D.E.; Maehara, Y.; Ponder, B.A.; et al. Dysregulation of PRMT1 and PRMT6, Type I arginine methyltransferases, is involved in various types of human cancers. Int. J. Cancer 2011, 128, 562–573. [Google Scholar]
  48. Smith, C.L.; Anthony, S.; Hubank, M.; Leiper, J.M.; Vallance, P. Effects of ADMA upon gene expression: An insight into the pathophysiological significance of raised plasma ADMA. PLoS Med 2005, 2, e264. [Google Scholar]
  49. 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, 572–575. [Google Scholar]
  50. Harrison, M.J.; Tang, Y.H.; Dowhan, D.H. Protein arginine methyltransferase 6 regulates multiple aspects of gene expression. Nucleic Acids Res 2010, 38, 2201–2216. [Google Scholar] [Green Version]
  51. Michaud-Levesque, J.; Richard, S. Thrombospondin-1 is a transcriptional repression target of PRMT6. J. Biol. Chem 2009, 284, 21338–21346. [Google Scholar]
  52. Dowhan, D.H.; Harrison, M.J.; Eriksson, N.A.; Bailey, P.; Pearen, M.A.; Fuller, P.J.; Funder, J.W.; Simpson, E.R.; Leedman, P.J.; Tilley, W.D.; et al. Protein arginine methyltransferase 6-dependent gene expression and splicing: Association with breast cancer outcomes. Endocr. Relat. Cancer 2012, 19, 509–526. [Google Scholar]
  53. Zhong, J.; Cao, R.X.; Zu, X.Y.; Hong, T.; Yang, J.; Liu, L.; Xiao, X.H.; Ding, W.J.; Zhao, Q.; Liu, J.H.; et al. Identification and characterization of novel spliced variants of PRMT2 in breast carcinoma. FEBS J 2012, 279, 316–335. [Google Scholar]
  54. El Messaoudi, S.; Fabbrizio, E.; Rodriguez, C.; Chuchana, P.; Fauquier, L.; Cheng, D.; Theillet, C.; Vandel, L.; Bedford, M.T.; Sardet, C. Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the Cyclin E1 gene. Proc. Natl. Acad. Sci. USA 2006, 103, 13351–13356. [Google Scholar]
  55. Majumder, S.; Liu, Y.; Ford, O.H., III; Mohler, J.L.; Whang, Y.E. Involvement of arginine methyltransferase CARM1 in androgen receptor function and prostate cancer cell viability. Prostate 2006, 66, 1292–1301. [Google Scholar]
  56. Frietze, S.; Lupien, M.; Silver, P.A.; Brown, M. CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res 2008, 68, 301–306. [Google Scholar]
  57. Hong, H.; Kao, C.; Jeng, M.H.; Eble, J.N.; Koch, M.O.; Gardner, T.A.; Zhang, S.; Li, L.; Pan, C.X.; Hu, Z.; et al. Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status. Cancer 2004, 101, 83–89. [Google Scholar]
  58. Ou, C.Y.; LaBonte, M.J.; Manegold, P.C.; So, A.Y.; Ianculescu, I.; Gerke, D.S.; Yamamoto, K.R.; Ladner, R.D.; Kahn, M.; Kim, J.H.; et al. A coactivator role of CARM1 in the dysregulation of β-catenin activity in colorectal cancer cell growth and gene expression. Mol. Cancer Res 2011, 9, 660–670. [Google Scholar]
  59. Ohira, T.; Gemmill, R.M.; Ferguson, K.; Kusy, S.; Roche, J.; Brambilla, E.; Zeng, C.; Baron, A.; Bemis, L.; Erickson, P.; et al. WNT7a induces E-cadherin in lung cancer cells. Proc. Natl. Acad. Sci. USA 2003, 100, 10429–10434. [Google Scholar]
  60. Yue, W.; Sun, Q.; Dacic, S.; Landreneau, R.J.; Siegfried, J.M.; Yu, J.; Zhang, L. Downregulation of Dkk3 activates β-catenin/TCF-4 signaling in lung cancer. Carcinogenesis 2008, 29, 84–92. [Google Scholar]
  61. O’Brien, K.B.; Alberich-Jorda, M.; Yadav, N.; Kocher, O.; Diruscio, A.; Ebralidze, A.; Levantini, E.; Sng, N.J.; Bhasin, M.; Caron, T.; et al. CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells. Development 2010, 137, 2147–2156. [Google Scholar]
  62. 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, L18–L24. [Google Scholar]
  63. Hong, E.; Lim, Y.; Lee, E.; Oh, M.; Kwon, D. Tissue-specific and age-dependent expression of protein arginine methyltransferases (PRMTs) in male rat tissues. Biogerontology 2012, 13, 329–336. [Google Scholar]
  64. Cho, E.C.; Zheng, S.; Munro, S.; Liu, G.; Carr, S.M.; Moehlenbrink, J.; Lu, Y.C.; Stimson, L.; Khan, O.; Konietzny, R.; et al. Arginine methylation controls growth regulation by E2F-1. EMBO J 2012, 31, 1785–1797. [Google Scholar]
  65. Lim, J.H.; Choi, Y.J.; Cho, C.H.; Park, J.W. Protein arginine methyltransferase 5 is an essential component of the hypoxia-inducible factor 1 signaling pathway. Biochem. Biophys. Res. Commun 2012, 418, 254–259. [Google Scholar]
  66. Powers, M.A.; Fay, M.M.; Factor, R.E.; Welm, A.L.; Ullman, K.S. Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4. Cancer Res 2011, 71, 5579–5587. [Google Scholar]
  67. Jansson, M.; Durant, S.T.; Cho, E.C.; Sheahan, S.; Edelmann, M.; Kessler, B.; La Thangue, N.B. Arginine methylation regulates the p53 response. Nat. Cell Biol 2008, 10, 1431–1439. [Google Scholar]
  68. Hainaut, P.; Hollstein, M. p53 and human cancer: The first ten thousand mutations. Adv. Cancer Res 2000, 77, 81–137. [Google Scholar]
  69. Shangary, S.; Wang, S. Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: A novel approach for cancer therapy. Annu. Rev. Pharmacol. Toxicol 2009, 49, 223–241. [Google Scholar]
  70. Fridman, J.S.; Lowe, S.W. Control of apoptosis by p53. Oncogene 2003, 22, 9030–9040. [Google Scholar]
  71. Vousden, K.H.; Lu, X. Live or let die: The cell’s response to p53. Nat. Rev. Cancer 2002, 2, 594–604. [Google Scholar]
  72. Breuer, R.H.; Postmus, P.E.; Smit, E.F. Molecular pathology of non-small-cell lung cancer. Respiration 2005, 72, 313–330. [Google Scholar]
  73. Martinez, F.J.; Safrin, S.; Weycker, D.; Starko, K.M.; Bradford, W.Z.; King, T.E., Jr; Flaherty, K.R.; Schwartz, D.A.; Noble, P.W.; Raghu, G.; et al. The clinical course of patients with idiopathic pulmonary fibrosis. Ann. Intern. Med. 2005, 142, 963–967. [Google Scholar]
  74. Thannickal, V.J.; Toews, G.B.; White, E.S.; Lynch, J.P., III; Martinez, F.J. Mechanisms of pulmonary fibrosis. Annu. Rev. Med. 2004, 55, 395–417. [Google Scholar]
  75. Du Bois, R.M. Strategies for treating idiopathic pulmonary fibrosis. Nat. Rev. Drug Discov 2010, 9, 129–140. [Google Scholar]
  76. Li, X.; Rayford, H.; Uhal, B.D. Essential roles for angiotensin receptor AT1a in bleomycin-induced apoptosis and lung fibrosis in mice. Am. J. Pathol 2003, 163, 2523–2530. [Google Scholar]
  77. Konigshoff, M.; Wilhelm, A.; Jahn, A.; Sedding, D.; Amarie, O.V.; 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, 640–650. [Google Scholar]
  78. Wygrecka, M.; Zakrzewicz, D.; Taborski, B.; Didiasova, M.; Kwapiszewska, G.; Preissner, K.T.; Markart, P. TGF-β1 induces tissue factor expression in human lung fibroblasts in a PI3K/JNK/Akt- and AP-1-dependent manner. Am. J. Respir. Cell Mol. Biol 2012. [Google Scholar] [CrossRef]
  79. Scotton, C.J.; Krupiczojc, M.A.; Konigshoff, M.; Mercer, P.F.; Lee, Y.C.; Kaminski, N.; Morser, J.; Post, J.M.; Maher, T.M.; Nicholson, A.G.; et al. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J. Clin. Invest 2009, 119, 2550–2563. [Google Scholar]
  80. Jablonska, E.; Markart, P.; Zakrzewicz, D.; Preissner, K.T.; Wygrecka, M. Transforming growth factor-β1 induces expression of human coagulation factor XII via Smad3 and JNK signaling pathways in human lung fibroblasts. J. Biol. Chem 2010, 285, 11638–11651. [Google Scholar]
  81. Wang, R.; Ramos, C.; Joshi, I.; Zagariya, A.; Pardo, A.; Selman, M.; Uhal, B.D. Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides. Am. J. Physiol 1999, 277, L1158–L1164. [Google Scholar]
  82. Papp, M.; Li, X.; Zhuang, J.; Wang, R.; Uhal, B.D. Angiotensin receptor subtype AT(1) mediates alveolar epithelial cell apoptosis in response to ANG II. Am. J. Physiol. Lung Cell Mol. Physiol 2002, 282, L713–L718. [Google Scholar]
  83. Lee, Y.H.; Mungunsukh, O.; Tutino, R.L.; Marquez, A.P.; Day, R.M. Angiotensin-II-induced apoptosis requires regulation of nucleolin and Bcl-xL by SHP-2 in primary lung endothelial cells. J. Cell Sci 2010, 123, 1634–1643. [Google Scholar]
  84. Bataller, R.; Sancho-Bru, P.; Gines, P.; Brenner, D.A. Liver fibrogenesis: A new role for the renin-angiotensin system. Antioxid. Redox Signal 2005, 7, 1346–1355. [Google Scholar]
  85. Ding, G.; Zhang, A.; Huang, S.; Pan, X.; Zhen, G.; Chen, R.; Yang, T. ANG II induces c-Jun NH2-terminal kinase activation and proliferation of human mesangial cells via redox-sensitive transactivation of the EGFR. Am. J. Physiol. Renal. Physiol 2007, 293, F1889–F1897. [Google Scholar]
  86. Huang, S.; Zhang, A.; Ding, G.; Chen, R. Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation. Am. J. Physiol. Renal. Physiol 2009, 296, F1323–F1333. [Google Scholar]
  87. Li, X.; Zhang, H.; Soledad-Conrad, V.; Zhuang, J.; Uhal, B.D. Bleomycin-induced apoptosis of alveolar epithelial cells requires angiotensin synthesis de novo. Am. J. Physiol. Lung Cell Mol. Physiol 2003, 284, L501–L507. [Google Scholar]
  88. Jacobi, J.; Maas, R.; Cordasic, N.; Koch, K.; Schmieder, R.E.; Boger, R.H.; Hilgers, K.F. Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice. Am. J. Physiol. Heart Circ. Physiol 2008, 294, H1058–H1066. [Google Scholar]
  89. Chen, M.F.; Xie, X.M.; Yang, T.L.; Wang, Y.J.; Zhang, X.H.; Luo, B.L.; Li, Y.J. Role of asymmetric dimethylarginine in inflammatory reactions by angiotensin II. J. Vasc. Res 2007, 44, 391–402. [Google Scholar]
  90. Manoury, B.; Nenan, S.; Leclerc, O.; Guenon, I.; Boichot, E.; Planquois, J.M.; Bertrand, C.P.; Lagente, V. The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis. Respir. Res 2005, 6, 11. [Google Scholar]
  91. Psathakis, K.; Mermigkis, D.; Papatheodorou, G.; Loukides, S.; Panagou, P.; Polychronopoulos, V.; Siafakas, N.M.; Bouros, D. Exhaled markers of oxidative stress in idiopathic pulmonary fibrosis. Eur. J. Clin. Invest 2006, 36, 362–367. [Google Scholar]
  92. Hassa, P.O.; Covic, M.; Bedford, M.T.; Hottiger, M.O. Protein arginine methyltransferase 1 coactivates NF-κB-dependent gene expression synergistically with CARM1 and PARP1. J. Mol. Biol 2008, 377, 668–678. [Google Scholar]
  93. Bond, M.; Chase, A.J.; Baker, A.H.; Newby, A.C. Inhibition of transcription factor NF-κB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells. Cardiovasc. Res 2001, 50, 556–565. [Google Scholar]
  94. Li, J.; Lau, G.K.; Chen, L.; Dong, S.S.; Lan, H.Y.; Huang, X.R.; Li, Y.; Luk, J.M.; Yuan, Y.F.; Guan, X.Y. Interleukin 17A promotes hepatocellular carcinoma metastasis via NF-κB induced matrix metalloproteinases 2 and 9 expression. PLoS One 2011, 6, e21816. [Google Scholar]
  95. Bond, M.; Fabunmi, R.P.; Baker, A.H.; Newby, A.C. Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: An absolute requirement for transcription factor NF-κB. FEBS Lett 1998, 435, 29–34. [Google Scholar]
  96. Rippe, R.A.; Schrum, L.W.; Stefanovic, B.; Solis-Herruzo, J.A.; Brenner, D.A. NF-κB inhibits expression of the α1(I) collagen gene. DNA Cell Biol 1999, 18, 751–761. [Google Scholar]
  97. Chang, Y.I.; Hua, W.K.; Yao, C.L.; Hwang, S.M.; Hung, Y.C.; Kuan, C.J.; Leou, J.S.; Lin, W.J. Protein-arginine methyltransferase 1 suppresses megakaryocytic differentiation via modulation of the p38 MAPK pathway in K562 cells. J. Biol. Chem 2010, 285, 20595–20606. [Google Scholar]
  98. 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, L34–L45. [Google Scholar]
  99. Moore, B.B.; Hogaboam, C.M. Murine models of pulmonary fibrosis. Am. J. Physiol. Lung Cell Mol. Physiol 2008, 294, L152–L160. [Google Scholar]
  100. Moeller, A.; Ask, K.; Warburton, D.; Gauldie, J.; Kolb, M. The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int. J. Biochem. Cell Biol 2008, 40, 362–382. [Google Scholar]
  101. Guccione, E.; Bassi, C.; Casadio, F.; Martinato, F.; Cesaroni, M.; Schuchlautz, H.; Luscher, B.; Amati, B. Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive. Nature 2007, 449, 933–937. [Google Scholar]
  102. Chen, H.; Herndon, M.E.; Lawler, J. The cell biology of thrombospondin-1. Matrix Biol 2000, 19, 597–614. [Google Scholar]
  103. Crawford, S.E.; Stellmach, V.; Murphy-Ullrich, J.E.; Ribeiro, S.M.; Lawler, J.; Hynes, R.O.; Boivin, G.P.; Bouck, N. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 1998, 93, 1159–1170. [Google Scholar]
  104. Ghofrani, H.A.; Wilkins, M.W.; Rich, S. Uncertainties in the diagnosis and treatment of pulmonary arterial hypertension. Circulation 2008, 118, 1195–1201. [Google Scholar]
  105. Puri, A.; McGoon, M.D.; Kushwaha, S.S. Pulmonary arterial hypertension: Current therapeutic strategies. Nat. Clin. Pract. Cardiovasc. Med 2007, 4, 319–329. [Google Scholar]
  106. Ghofrani, H.A.; Barst, R.J.; Benza, R.L.; Champion, H.C.; Fagan, K.A.; Grimminger, F.; Humbert, M.; Simonneau, G.; Stewart, D.J.; Ventura, C.; et al. Future perspectives for the treatment of pulmonary arterial hypertension. J. Am. Coll. Cardiol 2009, 54, S108–S117. [Google Scholar]
  107. Rubin, L.J. Pulmonary arterial hypertension. Proc. Am. Thorac. Soc 2006, 3, 111–115. [Google Scholar]
  108. Dweik, R.A. The lung in the balance: Arginine, methylated arginines, and nitric oxide. Am. J. Physiol. Lung Cell Mol. Physiol 2007, 292, L15–L17. [Google Scholar]
  109. Gorenflo, M.; Zheng, C.; Werle, E.; Fiehn, W.; Ulmer, H.E. Plasma levels of asymmetrical dimethyl-L-arginine in patients with congenital heart disease and pulmonary hypertension. J. Cardiovasc. Pharmacol 2001, 37, 489–492. [Google Scholar]
  110. Pullamsetti, S.; Kiss, L.; Ghofrani, H.A.; Voswinckel, R.; Haredza, P.; Klepetko, W.; Aigner, C.; Fink, L.; Muyal, J.P.; Weissmann, N.; et al. Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension. FASEB J 2005, 19, 1175–1177. [Google Scholar]
  111. Kielstein, J.T.; Bode-Boger, S.M.; Hesse, G.; Martens-Lobenhoffer, J.; Takacs, A.; Fliser, D.; Hoeper, M.M. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler. Thromb. Vasc. Biol 2005, 25, 1414–1418. [Google Scholar]
  112. Skoro-Sajer, N.; Mittermayer, F.; Panzenboeck, A.; Bonderman, D.; Sadushi, R.; Hitsch, R.; Jakowitsch, J.; Klepetko, W.; Kneussl, M.P.; Wolzt, M.; et al. Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension. Am. J. Respir. Crit. Care Med 2007, 176, 1154–1160. [Google Scholar]
  113. Landburg, P.P.; Teerlink, T.; van Beers, E.J.; Muskiet, F.A.; Kappers-Klunne, M.C.; van Esser, J.W.; Mac Gillavry, M.R.; Biemond, B.J.; Brandjes, D.P.; Duits, A.J.; et al. Association of asymmetric dimethylarginine with sickle cell disease-related pulmonary hypertension. Haematologica 2008, 93, 1410–1412. [Google Scholar]
  114. Dimitroulas, T.; Giannakoulas, G.; Sfetsios, T.; Karvounis, H.; Dimitroula, H.; Koliakos, G.; Settas, L. Asymmetrical dimethylarginine in systemic sclerosis-related pulmonary arterial hypertension. Rheumatology (Oxford UK) 2008, 47, 1682–1685. [Google Scholar]
  115. 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 Mol. Physiol 2007, 292, L1480–L1487. [Google Scholar]
  116. Millatt, L.J.; Whitley, G.S.; Li, D.; Leiper, J.M.; Siragy, H.M.; Carey, R.M.; Johns, R.A. Evidence for dysregulation of dimethylarginine dimethylaminohydrolase I in chronic hypoxia-induced pulmonary hypertension. Circulation 2003, 108, 1493–1498. [Google Scholar]
  117. Arrigoni, F.I.; Vallance, P.; Haworth, S.G.; Leiper, J.M. Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia. Circulation 2003, 107, 1195–1201. [Google Scholar]
  118. Zakrzewicz, D. Asymmetric dimethylarginine metabolism and its involvement in the pathogenesis of pulmonary arterial hypertension. Ph.D. Thesis, Justus-Liebig-Universität Gießen, Giessen, Germany, September 2008. [Google Scholar]
  119. Stockley, R.A.; Mannino, D.; Barnes, P.J. Burden and pathogenesis of chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc 2009, 6, 524–526. [Google Scholar]
  120. Stockley, R.A. Progression of chronic obstructive pulmonary disease: Impact of inflammation, comorbidities and therapeutic intervention. Curr. Med. Res. Opin 2009, 25, 1235–1245. [Google Scholar]
  121. Holgate, S.T. Pathogenesis of asthma. Clin. Exp. Allergy 2008, 38, 872–897. [Google Scholar]
  122. Parry, R.V.; Ward, S.G. Protein arginine methylation: a new handle on T lymphocytes? Trends Immunol 2010, 31, 164–169. [Google Scholar]
  123. Mowen, K.A.; Schurter, B.T.; Fathman, J.W.; David, M.; Glimcher, L.H. Arginine methylation of NIP45 modulates cytokine gene expression in effector T lymphocytes. Mol. Cell 2004, 15, 559–571. [Google Scholar]
  124. Mowen, K.A.; Tang, J.; Zhu, W.; Schurter, B.T.; Shuai, K.; Herschman, H.R.; David, M. Arginine methylation of STAT1 modulates IFNα/β-induced transcription. Cell 2001, 104, 731–741. [Google Scholar]
  125. Zakrzewicz, D.; Zakrzewicz, A.; Wilker, S.; Boedeker, R.H.; Padberg, W.; Eickelberg, O.; Grau, V. Dimethylarginine metabolism during acute and chronic rejection of rat renal allografts. Nephrol. Dial. Transplant 2011, 26, 124–135. [Google Scholar]
  126. Ahmad, T.; Mabalirajan, U.; Ghosh, B.; Agrawal, A. Altered asymmetric dimethyl arginine metabolism in allergically inflamed mouse lungs. Am. J. Respir. Cell Mol. Biol 2010, 42, 3–8. [Google Scholar]
  127. Scott, J.A.; North, M.L.; Rafii, M.; Huang, H.; Pencharz, P.; Subbarao, P.; Belik, J.; Grasemann, H. Asymmetric dimethylarginine is increased in asthma. Am. J. Respir. Crit. Care Med 2011, 184, 779–785. [Google Scholar]
  128. Klein, E.; Weigel, J.; Buford, M.C.; Holian, A.; Wells, S.M. Asymmetric dimethylarginine potentiates lung inflammation in a mouse model of allergic asthma. Am. J. Physiol. Lung Cell Mol. Physiol 2010, 299, L816–L825. [Google Scholar]
  129. Sun, Q.; Yang, X.; Zhong, B.; Jiao, F.; Li, C.; Li, D.; Lan, X.; Sun, J.; Lu, S. Upregulated protein arginine methyltransferase 1 by IL-4 increases eotaxin-1 expression in airway epithelial cells and participates in antigen-induced pulmonary inflammation in rats. J. Immunol 2012, 188, 3506–3512. [Google Scholar]
  130. Eid, H.M.; Arnesen, H.; Hjerkinn, E.M.; Lyberg, T.; Seljeflot, I. Relationship between obesity, smoking, and the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine. Metabolism 2004, 53, 1574–1579. [Google Scholar]
  131. Maas, R.; Schulze, F.; Baumert, J.; Lowel, H.; Hamraz, K.; Schwedhelm, E.; Koenig, W.; Boger, R.H. 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, 693–701. [Google Scholar]
Figure 1. The mechanism of protein arginine methylation in mammalian cells. L-Arg can be monomethylated on a guanidino nitrogen atom by all protein arginine methyltransferases (PRMTs). Type I PRMTs catalyze the formation of asymmetric dimethylarginine, while type II PRMTs generate symmetric dimmethylarginine. The donor of methyl groups is S-adenosylmethionine (AdoMet), which is further converted to S-adenosylhomocysteine (AdoHcy).
Figure 1. The mechanism of protein arginine methylation in mammalian cells. L-Arg can be monomethylated on a guanidino nitrogen atom by all protein arginine methyltransferases (PRMTs). Type I PRMTs catalyze the formation of asymmetric dimethylarginine, while type II PRMTs generate symmetric dimmethylarginine. The donor of methyl groups is S-adenosylmethionine (AdoMet), which is further converted to S-adenosylhomocysteine (AdoHcy).
Ijms 13 12383f1
Figure 2. Dysregulation of PRMTs in human and experimental pulmonary diseases. Members of the PRMT family and potential mechanisms of their action in the development and progression of pulmonary diseases (PD) are indicated. Arrows demonstrate PRMTs expression status, which has previously been reported in the literature. ↑, enhanced expression; ↓, impaired expression.
Figure 2. Dysregulation of PRMTs in human and experimental pulmonary diseases. Members of the PRMT family and potential mechanisms of their action in the development and progression of pulmonary diseases (PD) are indicated. Arrows demonstrate PRMTs expression status, which has previously been reported in the literature. ↑, enhanced expression; ↓, impaired expression.
Ijms 13 12383f2

Share and Cite

MDPI and ACS Style

Zakrzewicz, D.; Zakrzewicz, A.; Preissner, K.T.; Markart, P.; Wygrecka, M. Protein Arginine Methyltransferases (PRMTs): Promising Targets for the Treatment of Pulmonary Disorders. Int. J. Mol. Sci. 2012, 13, 12383-12400.

AMA Style

Zakrzewicz D, Zakrzewicz A, Preissner KT, Markart P, Wygrecka M. Protein Arginine Methyltransferases (PRMTs): Promising Targets for the Treatment of Pulmonary Disorders. International Journal of Molecular Sciences. 2012; 13(10):12383-12400.

Chicago/Turabian Style

Zakrzewicz, Dariusz, Anna Zakrzewicz, Klaus T. Preissner, Philipp Markart, and Malgorzata Wygrecka. 2012. "Protein Arginine Methyltransferases (PRMTs): Promising Targets for the Treatment of Pulmonary Disorders" International Journal of Molecular Sciences 13, no. 10: 12383-12400.

Article Metrics

Back to TopTop