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The Arginine/ADMA Ratio Is Related to the Prevention of Atherosclerotic Plaques in Hypercholesterolemic Rabbits When Giving a Combined Therapy with Atorvastatine and Arginine.

Brinkmann SJ, Wörner EA, Buijs N, Richir M, Cynober L, van Leeuwen PA, Couderc R - Int J Mol Sci (2015)

Bottom Line: The decrease in ADMA levels over time was significantly correlated to fewer aortic lesions in the distal aorta and total aorta.The arginine/ADMA ratio was correlated to cholesterol levels and decrease in cholesterol levels over time in the SA group.A lower arginine/ADMA ratio was significantly correlated to lower NO levels in the S and C group.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, VU University Medical Center, 1081 HV Amsterdam, The Netherlands. sj.brinkmann@vumc.nl.

ABSTRACT

Unlabelled: Supplementation with arginine in combination with atorvastatin is more efficient in reducing the size of an atherosclerotic plaque than treatment with a statin or arginine alone in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits. We evaluated the mechanism behind this feature by exploring the role of the arginine/asymmetric dimethylarginine (ADMA) ratio, which is the substrate and inhibitor of nitric oxide synthase (NOS) and thereby nitric oxide (NO), respectively.

Methods: Rabbits were fed either an arginine diet (group A, n = 9), standard rabbit chow plus atorvastatin (group S, n = 8), standard rabbit chow plus an arginine diet with atorvastatin (group SA, n = 8) or standard rabbit chow (group C, n = 9) as control. Blood was sampled and the aorta was harvested for topographic and histological analysis. Plasma levels of arginine, ADMA, cholesterol and nitric oxide were determined and the arginine/ADMA ratio was calculated.

Results: The decrease in ADMA levels over time was significantly correlated to fewer aortic lesions in the distal aorta and total aorta. The arginine/ADMA ratio was correlated to cholesterol levels and decrease in cholesterol levels over time in the SA group. A lower arginine/ADMA ratio was significantly correlated to lower NO levels in the S and C group.

Discussion: A balance between arginine and ADMA is an important indicator in the prevention of the development of atherosclerotic plaques.

No MeSH data available.


Related in: MedlinePlus

Schematic overview of the interactions between arginine, asymmetric dimethylarginine (ADMA), dimethylarginine dimethylaminohydrolase (DDAH), and nitric oxide synthase (NOS). PRMTs, protein arginine methyltransferases.
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ijms-16-12230-f001: Schematic overview of the interactions between arginine, asymmetric dimethylarginine (ADMA), dimethylarginine dimethylaminohydrolase (DDAH), and nitric oxide synthase (NOS). PRMTs, protein arginine methyltransferases.

Mentions: The formation of atherosclerosis can be overcome by increasing the synthesis of NO and providing its precursor arginine as a substrate to the endothelial cell [3]. Arginine is a semi-conditionally amino acid, which in its turn is the substrate for nitric oxide synthase (NOS) (see Figure 1). NOS converts arginine into NO and citrulline [4]. It has been shown that arginine supplementation increases NO availability, improves vascular responsiveness and reduces atherosclerosis in animals and patients [3,5]. Furthermore, endogenously produced inhibitors of the enzyme NOS, in particular asymmetric dimethylarginine (ADMA), also have an important role in NO metabolism [6,7]. ADMA and other methylarginines are continuously formed from intracellular proteolysis of methylated arginine residues in the nucleus of the cell, by enzymes called protein arginine methyltransferases (PRMTs) [8]. Whereas the structure of ADMA is similar to arginine, it competes with arginine for NOS binding, hereby blocking the formation of NO from arginine by NOS directly. NOS is mainly localized in the cell, thus the intracellular ADMA and arginine levels regulate NOS activity [9]. In addition, extracellular ADMA is an antagonist to extracellular arginine on cell membrane transporter level, whereas they are both transported into the cell via the cell membrane by the cationic amino acid transporter (y+ system), a high-affinity, Na+-independent transporter of the basic amino acids and therefore also compete with each other on this level [10]. Since ADMA competes with arginine for NOS and for cell transport via CAT-2, the bioavailability of NO depends on the balance between the two, the so-called arginine/ADMA ratio [11]. The arginine/ADMA ratio is an important indicator of NO bioavailability and therefore of the risk of formation of atherosclerotic plaques [11].


The Arginine/ADMA Ratio Is Related to the Prevention of Atherosclerotic Plaques in Hypercholesterolemic Rabbits When Giving a Combined Therapy with Atorvastatine and Arginine.

Brinkmann SJ, Wörner EA, Buijs N, Richir M, Cynober L, van Leeuwen PA, Couderc R - Int J Mol Sci (2015)

Schematic overview of the interactions between arginine, asymmetric dimethylarginine (ADMA), dimethylarginine dimethylaminohydrolase (DDAH), and nitric oxide synthase (NOS). PRMTs, protein arginine methyltransferases.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490441&req=5

ijms-16-12230-f001: Schematic overview of the interactions between arginine, asymmetric dimethylarginine (ADMA), dimethylarginine dimethylaminohydrolase (DDAH), and nitric oxide synthase (NOS). PRMTs, protein arginine methyltransferases.
Mentions: The formation of atherosclerosis can be overcome by increasing the synthesis of NO and providing its precursor arginine as a substrate to the endothelial cell [3]. Arginine is a semi-conditionally amino acid, which in its turn is the substrate for nitric oxide synthase (NOS) (see Figure 1). NOS converts arginine into NO and citrulline [4]. It has been shown that arginine supplementation increases NO availability, improves vascular responsiveness and reduces atherosclerosis in animals and patients [3,5]. Furthermore, endogenously produced inhibitors of the enzyme NOS, in particular asymmetric dimethylarginine (ADMA), also have an important role in NO metabolism [6,7]. ADMA and other methylarginines are continuously formed from intracellular proteolysis of methylated arginine residues in the nucleus of the cell, by enzymes called protein arginine methyltransferases (PRMTs) [8]. Whereas the structure of ADMA is similar to arginine, it competes with arginine for NOS binding, hereby blocking the formation of NO from arginine by NOS directly. NOS is mainly localized in the cell, thus the intracellular ADMA and arginine levels regulate NOS activity [9]. In addition, extracellular ADMA is an antagonist to extracellular arginine on cell membrane transporter level, whereas they are both transported into the cell via the cell membrane by the cationic amino acid transporter (y+ system), a high-affinity, Na+-independent transporter of the basic amino acids and therefore also compete with each other on this level [10]. Since ADMA competes with arginine for NOS and for cell transport via CAT-2, the bioavailability of NO depends on the balance between the two, the so-called arginine/ADMA ratio [11]. The arginine/ADMA ratio is an important indicator of NO bioavailability and therefore of the risk of formation of atherosclerotic plaques [11].

Bottom Line: The decrease in ADMA levels over time was significantly correlated to fewer aortic lesions in the distal aorta and total aorta.The arginine/ADMA ratio was correlated to cholesterol levels and decrease in cholesterol levels over time in the SA group.A lower arginine/ADMA ratio was significantly correlated to lower NO levels in the S and C group.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, VU University Medical Center, 1081 HV Amsterdam, The Netherlands. sj.brinkmann@vumc.nl.

ABSTRACT

Unlabelled: Supplementation with arginine in combination with atorvastatin is more efficient in reducing the size of an atherosclerotic plaque than treatment with a statin or arginine alone in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits. We evaluated the mechanism behind this feature by exploring the role of the arginine/asymmetric dimethylarginine (ADMA) ratio, which is the substrate and inhibitor of nitric oxide synthase (NOS) and thereby nitric oxide (NO), respectively.

Methods: Rabbits were fed either an arginine diet (group A, n = 9), standard rabbit chow plus atorvastatin (group S, n = 8), standard rabbit chow plus an arginine diet with atorvastatin (group SA, n = 8) or standard rabbit chow (group C, n = 9) as control. Blood was sampled and the aorta was harvested for topographic and histological analysis. Plasma levels of arginine, ADMA, cholesterol and nitric oxide were determined and the arginine/ADMA ratio was calculated.

Results: The decrease in ADMA levels over time was significantly correlated to fewer aortic lesions in the distal aorta and total aorta. The arginine/ADMA ratio was correlated to cholesterol levels and decrease in cholesterol levels over time in the SA group. A lower arginine/ADMA ratio was significantly correlated to lower NO levels in the S and C group.

Discussion: A balance between arginine and ADMA is an important indicator in the prevention of the development of atherosclerotic plaques.

No MeSH data available.


Related in: MedlinePlus