Disruption of methylarginine metabolism impairs vascular homeostasis

Leiper, James; Nandi, Manasi; Torondel, Belén; Murray‐Rust, Judith; Malaki, Mohammed; O'Hara, B.P.; Rossiter, Sharon; Anthony, Shelagh; Madhani, Melanie; Selwood, David L.; Smith, Caroline L.; Wójciak-Stothard, Beata; Rudiger, Alain; Stidwill, R; McDonald, Neil Q.; Vallance, Patrick

doi:10.1038/nm1543

Cited by 376 publications

(419 citation statements)

References 21 publications

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“…Numerous studies have demonstrated that overexpression of DDAH1 promotes angiogenesis in vitro and increases glioma growth in vivo through enhanced expression of NO and VEGF (Kostourou et al ., 2002; Smith et al ., 2003; Wojciak‐Stothard et al ., 2007). DDAH1 also plays a vital role in early embryogenesis (Breckenridge et al ., 2010; Leiper et al ., 2007). More recently, a study has shown that DDAH1 can inhibit the renal fibrosis process via the Wnt/β‐catenin pathway (Liu et al ., 2016), a well‐established crucial signaling event associated with a number of human diseases (Miao et al ., 2013; Miki et al ., 2011; de Sousa et al ., 2011) including cancer (Ramachandran et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

DDAH1 mediates gastric cancer cell invasion and metastasis via Wnt/β‐catenin signaling pathway

et al. 2017

Molecular Oncology

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Gastric cancer (GC) represents the fourth most common malignant neoplasm and the second leading cause of cancer death. Despite therapeutic advances in recent decades, the clinical outcome remains dismal owing to the fact that most patients with GC show advanced disease at diagnosis and current chemotherapy only confers a modest survival advantage. Identification of key molecular signaling pathways involved in gastric carcinogenesis and progression would aid in early diagnosis and provide a rational design for targeted therapies in selected patients with advanced GC, to improve their outcome. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the main enzyme that can degrade asymmetric dimethylarginine, an endogenous nitric oxide synthase (NOS) inhibitor. Increased DDAH1 expression and NO production have been linked to multiple pathological conditions including cancer. However, the prognostic significance of DDAH1 in patients with GC and its function in GC progression remain undefined. In this study, we found that downregulation of DDAH1 was frequently detected in GC tissues and strongly correlated with more aggressive phenotypes and poor prognosis. Functional assays confirmed that forced expression of DDAH1 in the GC cells suppressed cell migration and invasion in vitro, as well as metastatic potential in vivo. DDAH1 overexpression inhibited the epithelial–mesenchymal transition process by increasing β‐catenin degradation through the attenuation of Wnt/GSK‐3β signaling. In contrast, knockdown of DDAH1 produced the opposite effect. These findings suggest that DDAH1 functions as a tumor suppressor in GC and may be exploited as a diagnostic and prognostic biomarker for GC.

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Section: Introductionmentioning

confidence: 99%

DDAH1 mediates gastric cancer cell invasion and metastasis via Wnt/β‐catenin signaling pathway

et al. 2017

Molecular Oncology

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“…NO is mainly produced by endothelial NO synthase (eNOS) and endothelial dysfunction is characterized by a loss of NO bioavailability. Impairment of eNOS activity by endogenous inhibitors such as asymmetrical dimethylarginine (ADMA) in endothelial dysfunction-associated diseases has gained interest (Leiper et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Estradiol, acting through estrogen receptor alpha, restores dimethylarginine dimethylaminohydrolase activity and nitric oxide production in oxLDL-treated human arterial endothelial cells

Novella

Laguna-Fernández

Lázaro-Franco

et al. 2013

Molecular and Cellular Endocrinology

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a b s t r a c tAsymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase. ADMA accumulation, mainly due to a decreased dimethylarginine dimethylaminohydrolase (DDAH) activity, has been related to the development of cardiovascular diseases. We investigate whether estradiol prevents the changes induced by oxidized low density lipoprotein (oxLDL) on the DDAH/ADMA/NO pathway in human umbilical artery endothelial cells (HUAEC). HUAEC were exposed to estradiol, native LDL (nLDL), oxLDL and their combinations for 24 h. In some experiments, cells were also exposed to the unspecific estrogen receptor (ER) antagonist ICI 182780, the specific ERa antagonist MPP or specific agonists for ERa, ERb and GPER. ADMA concentration was measured by HPLC and concentration of NO by amperometry. Protein expression and DDAH activity were measured by immunoblotting and an enzymatic method, respectively. oxLDL, but not nLDL, increased ADMA concentration with a concomitant decrease on DDAH activity. oxLDL reduced eNOS protein and NO production. Estradiol alone had no effects on DDAH/ADMA/NO pathway, but increased the attenuated endothelial NO production induced by oxLDL by reduction in ADMA and preventing loss of eNOS protein levels. ICI 182780 and MPP completely abolished these effects of estradiol on oxLDL-exposed cells. ERa agonist, but not ERb and GPER agonists, mirrored estradiol effects on NO production. In conclusion, estradiol restores (1) DDAH activity, and therefore ADMA levels, and (2) NO production impaired by oxLDL in HUAEC acting through ERa.

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“…Thus far, elevated ADMA levels have been associated with all established cardiovascular risk factors (38). Furthermore, recent data from genetic mouse models indicate a causal role for ADMA in the pathophysiology of vascular disease (7,19). ADMA derives from the posttranslational methylation of L-arginine residues within proteins catalyzed by enzymes called protein arginine methyltransferases (PRMTs).…”

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confidence: 99%

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

Jacobi¹,

Maas²,

Cordasic³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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RH, Hilgers KF. Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice. Am J Physiol Heart Circ Physiol 294: H1058-H1066, 2008. First published December 21, 2007 doi:10.1152/ajpheart.01103.2007.-The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n ϭ 28) were treated with 1.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, 3.0 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage. dimethylarginine dimethylaminohydrolase; hypertension; transgenic ASYMMETRIC DIMETHYLARGININE (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is increasingly recognized as a potential risk factor and prognostic biomarker in cardiovascular disease (38). Thus far, elevated ADMA levels have been associated with all established cardiovascular risk factors (38). Furthermore, recent data from genetic mouse models indicate a causal role for ADMA in the pathophysiology of vascular disease (7,19). ADMA derives from the posttranslational methylation of L-arginine residues within proteins catalyzed by enzymes called protein arginine methyltransferases (PRMTs). Upon proteolysis, methylarginines are released into the circulation. Although ϳ15% of ADMA are excreted via the urine, the major elimination occurs through enzymatic degradation (ϳ85%) (1). The enzyme dimethylarginine dimethylaminohydrolase (DDAH), of which two isoforms with distinct tissue distribution have been described, catalyzes the hydrolysis of ADMA to L-citrulline and dimethylamine (38).Thus far, clinical studies have mostly addressed the prognostic value of ADMA in cardiovascular or kidney disease as well as the impact of pharmacological interventions aimed at lowering ADMA levels ...

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Disruption of methylarginine metabolism impairs vascular homeostasis

Abstract: There was an error published in J. Cell Sci. 120, 929-942. We apologise for the incorrect publication of a reference, for which the wrong year, title and journal details were given. The correct reference is shown below.

Cited by 376 publications

References 21 publications

DDAH1 mediates gastric cancer cell invasion and metastasis via Wnt/β‐catenin signaling pathway

DDAH1 mediates gastric cancer cell invasion and metastasis via Wnt/β‐catenin signaling pathway

Estradiol, acting through estrogen receptor alpha, restores dimethylarginine dimethylaminohydrolase activity and nitric oxide production in oxLDL-treated human arterial endothelial cells

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

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