Asymmetric Dimethylarginine: Clinical Significance and Novel Therapeutic Approaches

Tousoulis, Dimitris; Georgakis, Marios K.; Oikonomou, Evangelos; Papageorgiou, Nikolaos S.; Zaromitidou, Marina; Latsios, George; Papaioannou, Spyridon; Siasos, Gerasimos

doi:10.2174/0929867322666150625095046

Cited by 33 publications

(25 citation statements)

References 335 publications

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“…The asymmetric dimethylarginine (ADMA) serves as endogenous inhibitor of NOS, modulating NO synthesis in various tissues [ 28 , 29 , 30 ]. Changes in the ADMA levels or l -arginine/ADMA ratio have been noted in plasma of patients with acute liver failure [ 31 ], or with liver cirrhosis [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Ammonia Reduces Intracellular Asymmetric Dimethylarginine in Cultured Astrocytes Stimulating Its y+LAT2 Carrier-Mediated Loss

Milewski

Bogacińska-Karaś

Fręśko

et al. 2017

IJMS

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Previously we had shown that ammonia stimulates nitric oxide (NO) synthesis in astrocytes by increasing the uptake of the precursor amino acid, arginine via the heteromeric arginine/glutamine transporter y+LAT2. Ammonia also increases the concentration in the brain of the endogenous inhibitor of nitric oxide synthases (NOS), asymmetric dimethylarginine (ADMA), but distribution of ADMA surplus between the intraastrocytic and extracellular compartments of the brain has not been studied. Here we tested the hypothesis that ammonia modulates the distribution of ADMA and its analog symmetric dimethylarginine (SDMA) between the two compartments of the brain by competition with arginine for the y+LAT2 transporter. In extension of the hypothesis we analyzed the ADMA/Arg interaction in endothelial cells forming the blood-brain barrier. We measured by high-performance liquid chromatography (HPLC) and mass spectrometry (MS) technique the concentration of arginine, ADMA and SDMA in cultured cortical astrocytes and in a rat brain endothelial cell line (RBE-4) treated with ammonia and the effect of silencing the expression of a gene coding y+LAT2. We also tested the expression of ADMA metabolism enzymes: protein arginine methyltransferase (PRMT) and dimethylarginine dimethyl aminohydrolase (DDAH) and arginine uptake to astrocytes. Treatment for 48 h with 5 mM ammonia led to an almost 50% reduction of ADMA and SDMA concentration in both cell types, and the effect in astrocytes was substantially attenuated by silencing of the Slc7a6 gene. Moreover, the y+LAT2-dependent component of ammonia-evoked arginine uptake in astrocytes was reduced in the presence of ADMA in the medium. Our results suggest that increased ADMA efflux mediated by upregulated y+LAT2 may be a mechanism by which ammonia interferes with intra-astrocytic (and possibly intra-endothelial cell) ADMA content and subsequently, NO synthesis in both cell types.

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Section: Discussionmentioning

confidence: 99%

Ammonia Reduces Intracellular Asymmetric Dimethylarginine in Cultured Astrocytes Stimulating Its y+LAT2 Carrier-Mediated Loss

Milewski

Bogacińska-Karaś

Fręśko

et al. 2017

IJMS

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“…Se ha sugerido que la mayoría de los factores de riesgo cardiovascular ejercen sus efectos negativos sobre la función endotelial a través de una vía patogénica común que lleva a una acumulación del ADMA, un potente inhibidor de la sintasa de ON, lo cual provoca alteraciones de este al disminuir la vasodilatación y favorecer la agregación plaquetaria, la proliferación celular, la oxidación de las LDL, la aparición de radicales libres y otros factores que contribuyen a la formación y progresión del proceso aterosclerótico (Tousoulis et al, 2015). Más aún, las concentraciones de ADMA han sido propuestas como un factor de riesgo cardiovascular independiente (Bouras et al, 2016).…”

Section: Discussionunclassified

Dimetilarginina asimétrica plasmática en mujeres obesas y no obesas con síndrome de ovarios poliquísticos

Mejia-Montilla

Álvarez‐Mon

Torres-Cepeda

et al. 2016

ARS med

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“…One potential candidate is asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase, and hence, a key mediator of vascular function. 3 We have previously reported that higher levels of ADMA soon after transplant are associated with abnormal epicardial function and the development of accelerated CAV at 1-year in heart transplant recipients, both of which are known predictors of 5-year graft failure (i.e. death or re-transplantation).…”

Section: Introductionmentioning

confidence: 96%

Usefulness of Asymmetric Dimethylarginine to Predict Outcomes After Heart Transplantation

Parikh

Khush

Luikart

et al. 2018

The American Journal of Cardiology

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Asymmetric dimethylarginine (ADMA) is a key mediator of vascular homeostasis and an independent predictor of the development of accelerated cardiac allograft vasculopathy after heart transplantation. However, its association with clinical outcomes in heart transplant recipients has not been described. Plasma levels of ADMA were assayed within 8 weeks following transplantation (baseline) using a competitive enzyme-linked immunosorbent assay. The primary end point was the composite of nonfatal myocardial infarction, percutaneous coronary intervention, retransplantation, or death at 5-year follow-up. Kaplan-Meier curves were generated to assess the association between baseline ADMA levels (stratified at 0.70 µM, a previously established cutoff) and cumulative event-free survival. Multivariate Cox regression was performed to adjust for other candidate predictors. In 69 heart transplant recipients at Stanford, the primary end point occurred in 11 patients (16%)-4 percutaneous coronary intervention, 1 retransplant, and 6 deaths-during 5-years follow-up. Patients with baseline ADMA ≥0.70 µM had lower cumulative 5-year event-free survival (77% vs 93%, p = 0.059). In multivariate Cox analysis, baseline ADMA was the only significant predictor of the primary end point (hazard ratio 1.33, 95% confidence interval 1.03 to 1.72 per 0.1 µM; p = 0.031). This association remained significant even after restricting the end point to death or retransplantation (hazard ratio 1.48, 95% confidence interval 1.12 to 1.97 per 0.1 µM; p = 0.006). In conclusion, elevated baseline plasma levels of ADMA independently predicted 5-year clinical outcomes after heart transplantation, suggesting that ADMA has potential prognostic value in the heart transplant arena.

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Asymmetric Dimethylarginine: Clinical Significance and Novel Therapeutic Approaches

Cited by 33 publications

References 335 publications

Ammonia Reduces Intracellular Asymmetric Dimethylarginine in Cultured Astrocytes Stimulating Its y+LAT2 Carrier-Mediated Loss

Ammonia Reduces Intracellular Asymmetric Dimethylarginine in Cultured Astrocytes Stimulating Its y+LAT2 Carrier-Mediated Loss

Dimetilarginina asimétrica plasmática en mujeres obesas y no obesas con síndrome de ovarios poliquísticos

Usefulness of Asymmetric Dimethylarginine to Predict Outcomes After Heart Transplantation

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