Cardiovascular Biology of the Asymmetric Dimethylarginine:Dimethylarginine Dimethylaminohydrolase Pathway

Abstract

Abstract-An increasing number of reports indicate that endogenously produced inhibitors of nitric oxide synthase, particularly asymmetric dimethylarginine (ADMA), regulate nitric oxide generation in disease states. This article describes the biology of ADMA and the implications for cardiovascular physiology and pathophysiology. Key Words: asymmetric dimethylarginine Ⅲ dimethylarginine dimethylaminohydrolase Ⅲ nitric oxide synthase Ⅲ endothelial dysfunction A symmetric dimethylarginine (ADMA) is a naturally occurring amino acid that circulates in plasma, is excreted in urine, and is found in tissues and cells. [1][2][3] It has aroused interest because it inhibits nitric oxide synthases (NOSs) 1 and therefore has the potential to produce considerable biological effects, particularly in the cardiovascular system. Recently, several studies have suggested that the plasma concentrations of ADMA provide a marker of risk for endothelial dysfunction and cardiovascular disease. 1,4 -6 This article describes the biology of ADMA and the implications for cardiovascular physiology and pathophysiology. How Is ADMA Made?ADMA is synthesized when arginine residues in proteins are methylated by the action of protein arginine methyltransferases (PRMTs). 7,8 Protein arginine methylation is a posttranslational modification that adds either 1 or 2 methyl groups to the guanidine nitrogens of arginine incorporated into proteins. There are 2 broad types of PRMTs: type 1 catalyze the formation of ADMA, whereas type 2 methylate both of the guanidino nitrogens and so result in the formation of symmetric dimethylarginine (SDMA; Figure 1). Both types of PRMT, of which there are several isoforms, can also monomethylate, leading to the formation of N G -monomethyl-L-arginine (L-NMMA). 7,8 Once the proteins are hydrolyzed, free methylarginines appear in the cytosol. The asymmetrically methylated arginines (ADMA and L-NMMA) are inhibitors of NOS, whereas SDMA is not. There is potentially a very broad range of substrate proteins for type 1 PRMTs, 9 and the enzymes and their substrates are widely distributed throughout the body. 10 The role of protein arginine methylation is unclear, but this process has been implicated in regulation of RNA binding, transcriptional regulation, DNA repair, protein localization, protein-protein interaction, signal transduction, and recycling or desensitization of receptors. However, it is only after the proteins are degraded that free methylarginines appear in the cytosol; to date, no direct route of synthesizing ADMA from free arginine has been identified. Thus, the amount of ADMA generated within a cell is dependent on the extent of arginine methylation in proteins and the rates of protein turnover.Because of the complex process leading to generation of free ADMA, it is unclear whether ADMA generation is fairly constant, it alters with PRMT activity, or if rates of protein turnover are the most important influence. Recently, studies with relatively nonspecific and low-potency PRMT inhibitors have suggested that PR...

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

“…The absence of estradiol stimulation on DDAH-I protein expression is in accordance with previous studies performed in murine endothelial cells (Holden et al, 2003). In fact, the expression of DDAH-II, but not DDAH-I, protein has been shown to be transcriptionally regulated in endothelial cells (Vallance and Leiper, 2004).…”

Effect of supplementation with B vitamins and antioxidants on levels of asymmetric dimethylarginine (ADMA) and C-reactive protein (CRP): a double-blind, randomised, factorial design, placebo-controlled trial

“…ADMA is synthesised when arginine residues in proteins are methylated by the action of protein arginine N-methyltransferases (PRMTs) [6]. PRMT 1 is involved in the production of ADMA and is expressed in the heart, vascular smooth muscle cells and endothelial cells [6].…”

“…Once the proteins are hydrolysed, free methylated arginines are released into the cytosol. ADMA is excreted in the urine to some extent, but the major metabolic pathway is by degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH) [6]. Consequently, whereas impaired renal function may result in elevated levels of ADMA, attenuation of DDAH activity may play the key role in increasing ADMA levels in persons without renal complications [7].…”

Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover

“…Protein arginine N-methyltransferases catalyse the conversion of protein-bound arginine to NMMA, which may be further methylated by protein arginine N-methyltransferases I and II to form ADMA and SDMA, respectively. Free NMMA and ADMA are inhibitors of NOS, with different potencies for different isoforms, and both are competitive inhibitors of arginine transport, whereas SDMA only inhibits the transport of arginine [2,3], whose precise role at concentrations found in vivo remains to be defined [4].…”

“…However, the mechanism(s) that mediate elevations of plasma methylarginines are not completely understood. NMMA and ADMA are metabolised by dimethylarginine dimethylaminohydrolase (DDAH) to L-citrulline, and its activity regulates ADMA levels [4,7,9]. Control of circulating MA concentrations by the rates of protein turnover (especially of degradation) has not hitherto been studied in insulin-resistant humans.…”