Erythropoietin Increases Asymmetric Dimethylarginine in Endothelial Cells

Scalera, Fortunato; Kielstein, Jan T.; Martens‐Lobenhoffer, Jens; Postel, S.; Täger, Michael; Bode‐Böger, Stefanie M.

doi:10.1681/asn.2004090735

Cited by 90 publications

(67 citation statements)

References 38 publications

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“…15,65 Plasma ADMA, which has spilled out of the cells in which it was produced, is the measured variable. In vascular endothelium, ADMA levels are approximately 10-fold those of plasma, 66 and concentrations are extremely high in the kidney and spleen. 67 It is the local intracellular level of ADMA that regulates NOS activity 65 and this probably varies greatly between organs.…”

Section: Endogenous Nos Inhibitorsmentioning

confidence: 97%

Arginine, arginine analogs and nitric oxide production in chronic kidney disease

2006

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SummaryNitric oxide (NO) production is reduced in renal disease, partially due to decreased endothelial NO production. Evidence indicates that NO deficiency contributes to cardiovascular events and progression of kidney damage. Two possible causes of NO deficiency are substrate (L-arginine) limitation and increased levels of circulating endogenous inhibitors of NO synthase (particularly asymmetric dimethylarginine [ADMA]). Decreased L-arginine availability in chronic kidney disease (CKD) is due to perturbed renal biosynthesis of this amino acid. In addition, inhibition of transport of L-arginine into endothelial cells and shunting of L-arginine into other metabolic pathways (e.g. those involving arginase) might also decrease availability. Elevated plasma and tissue levels of ADMA in CKD are functions of both reduced renal excretion and reduced catabolism by dimethylarginine dimethylaminohydrolase (DDAH). The latter might be associated with loss-offunction polymorphisms of a DDAH gene, functional inhibition of the enzyme by oxidative stress in CKD and end-stage renal disease, or both. These findings provide the rationale for novel therapies, including supplementation of dietary L-arginine or its precursor L-citrulline, inhibition of non-NOproducing pathways of L-arginine utilization, or both. Because an increase in ADMA has emerged as a major independent risk factor in end-stage renal disease (and probably also in CKD), lowering ADMA concentration is a major therapeutic goal; interventions that enhance the activity of the ADMA-hydrolyzing enzyme DDAH are under investigation.

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Section: Endogenous Nos Inhibitorsmentioning

confidence: 97%

Arginine, arginine analogs and nitric oxide production in chronic kidney disease

2006

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“…HUVEC on third passage were cultured in endothelial basal medium that contained 70 mol/L arginine as described previously (27). After reaching confluence, endothelial cells were treated with SDMA (2, 5, 10, and 100 M), SDMA plus l-or d-arginine (200 and 400 M), or vehicle for 24 h as indicated for each experiment.…”

Section: Cell Culture Studiesmentioning

confidence: 99%

Symmetrical Dimethylarginine

Bode‐Böger

Scalera

Kielstein

et al. 2006

Journal of the American Society of Nephrology

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255

204

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Symmetrical dimethylarginine (SDMA) is the structural isomer of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine. Whereas the major route of asymmetric dimethylarginine elimination is the hydrolytic degradation by dimethylarginine dimethylaminohydrolase, SDMA is eliminated by renal excretion. SDMA does not directly inhibit NOS but is a competitor of arginine transport. This study showed for the first time that measurement of SDMA can be a marker of estimated GFR and extent of coronary artery disease (CAD). In 97 patients with CAD, SDMA was a marker of estimated GFR. On multiple regression analysis of the CAD parameter stenosis score, SDMA was the only parameter retained. In addition, endothelial cells from the third passage were cultured in medium that contained 70 mol/L arginine and was incubated for 24 h in the presence of various concentration of SDMA (0, 2, 5, 10, and 100 mol/L). The levels of nitrate and nitrite in conditioned media, the protein expression of NOS, and the content of reactive oxygen species in endothelial cells were determined. SDMA inhibited dose dependently the NO synthesis in intact endothelial cells, whereas it had no effect on protein expression of NOS. This effect was associated with an increase in reactive oxygen species. Co-incubation with S ymmetrical dimethylarginine (SDMA) is the structural isomer of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA). ADMA has been shown to correlate with risk factors for coronary artery disease (CAD) such as hypertension (1,2), hypercholesterolemia (3), hyperhomocysteinemia (4 -6), insulin resistance (7), age (1), and mean arterial pressure (1). Moreover, ADMA correlates with the extent and the severity of coronary atherosclerosis (8) and is a strong and independent marker of cardiovascular events and mortality in selected patient populations (9 -11). Although there is mounting evidence that chronically elevated ADMA may contribute to progression of vascular disease via endothelial damage, little attention has been paid to the role of SDMA. Both ADMA and SDMA derive from intranuclear methylation of l-arginine residuals and are released into the cytoplasm after proteolysis (12). SDMA is produced by protein-arginine methyltransferase 5 (PRMT 5) and PRMT 7 (both type II methyltransferases) (13,14). Only ADMA but not SDMA is metabolized by dimethylarginine dimethylaminohydrolase to citrulline and dimethylamine (15). SDMA seems to be strictly eliminated by renal excretion (16,17). A recent study by Fliser et al. (18) showed a very close correlation among serum creatinine, GFR (measured by iodothalamate clearance technique), and SDMA. The authors speculated that SDMA, equal to serum creatinine, can serve as a marker of renal function, but SDMA seems to be more than a simple indicator of renal function. In animals, a high-fat, high-cholesterol diet increases SDMA serum levels (19,20) without affecting renal function (20), indicating that cardiovascular risk factors other than impaired...

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“…A cysteine residue at the active site of DDAH has been proposed to be oxidised by homocysteine, this mechanism might account for lowered DDAH activity in hypercholesterolemia [146]. Erythropoietin therapy to treat anaemia has been reported to cause hypertension in some patients; and DDAH activity has been demonstrated to fall, oxidation of the active site cysteine was proposed to cause this effect [147].…”

Section: Regulation Of Adma Metabolismmentioning

confidence: 99%

“…There is conflicting evidence about TNF-polymorphisms and the effects on plasma CRP concentrations [187,189]. Carriers of a genetic variant in the Toll-like Glucose protein / activity [149] Erythropoietin activity [147] IL-1 activity [154] Oestrogen activity [155] Retinoic acid DDAHII mRNA/protein/activity [156] Shear stress DDAHI expression [157] en Identified.…”

Section: Polymorphisms Of Crpmentioning

confidence: 99%

C-Reactive Protein and Asymmetric Dimethylarginine: Markers or Mediators in Cardiovascular Disorders?

Smith¹

2007

CPD

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This is an electronic version of an article published in Current Pharmaceutical Design, 13 (16). pp. [1619][1620][1621][1622][1623][1624][1625][1626][1627][1628][1629] 2007. The definitive version is available online at:http://www.bentham.org/cpd/index.htmThe WestminsterResearch online digital archive at the University of Westminster aims to make the research output of the University available to a wider audience. Copyright and Moral Rights remain with the authors and/or copyright owners. Users are permitted to download and/or print one copy for non-commercial private study or research. Further distribution and any use of material from within this archive for profit-making enterprises or for commercial gain is strictly forbidden.Whilst further distribution of specific materials from within this archive is forbidden, you may freely distribute the URL of WestminsterResearch.(http://www.wmin.ac.uk/westminsterresearch).In case of abuse or copyright appearing without permission e-mail wattsn@wmin.ac.uk. Abstract: C-reactive protein (CRP) has received much attention as a cardiovascular risk factor and has been recommended to be used in screening to assist in predicting the occurrence of cardiovascular disorders. There are numerous association studies documenting changes in circulating CRP concentrations, there are, however, fewer studies providing evidence that CRP mediates the progression of cardiovascular pathologies. Elucidating the potential mechanisms for CRP has been confounded by recent reports that contaminants of CRP are partially responsible for observed effects.In this review the use of CRP as a tool to predict cardiovascular disorders will be discussed alongside a more recently described cardiovascular risk factor asymmetric dimethylarginine (ADMA). An endogenously occurring nitric oxide synthase inhibitor, ADMA, is formed by the action of protein arginine methyltransferases and subsequent proteolysis and it is metabolised in vivo by the dimethylarginine dimethylaminohydrolases (DDAH). The evidence available documenting the effects of CRP and ADMA, the regulatory mechanisms and the genetic influences, will be discussed in order to determine whether CRP and ADMA are mediators in the progression of cardiovascular disorders or merely useful biomarkers.

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Erythropoietin Increases Asymmetric Dimethylarginine in Endothelial Cells

Cited by 90 publications

References 38 publications

Arginine, arginine analogs and nitric oxide production in chronic kidney disease

Arginine, arginine analogs and nitric oxide production in chronic kidney disease

Symmetrical Dimethylarginine

C-Reactive Protein and Asymmetric Dimethylarginine: Markers or Mediators in Cardiovascular Disorders?

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