Journal of Thrombosis and Thrombolysis

, Volume 27, Issue 2, pp 168–171

Asymmetric dimethylarginine and impaired cardiovascular healing


    • Department of Cardiovascular MedicineCatholic University Medical School
    • Department of Cardiovascular MedicineCatholic University
  • Eleonora Santucci
    • Department of Cardiovascular MedicineCatholic University Medical School
  • Francesca Marzo
    • Department of Cardiovascular MedicineCatholic University Medical School
  • Felicita Andreotti
    • Department of Cardiovascular MedicineCatholic University Medical School

DOI: 10.1007/s11239-007-0181-y

Cite this article as:
Coluzzi, G., Santucci, E., Marzo, F. et al. J Thromb Thrombolysis (2009) 27: 168. doi:10.1007/s11239-007-0181-y


Asymmetric dimethylarginine (ADMA) typically accumulates in the plasma of patients with chronic renal failure. Moreover, its plasma levels are raised in the presence of virtually all of the traditional cardiovascular risk factors. ADMA inhibits the three isoforms of nitric oxide (NO) synthase, thereby blunting the known cardioprotective effects of NO. Through its NO inhibitor actions, ADMA also exerts pro-apoptotic effects and suppresses progenitor cell mobilization, differentiation and function. Among patients with ischemic heart disease, low progenitor cell bioavailability and kidney dysfunction are emerging as strong predictors of death and recurrent cardiovascular events. We propose that patients with ischemic heart disease, kidney dysfunction, and high risk factor burden exhibit adverse cardiovascular outcomes, at least in part, through ADMA-mediated NO depression, enhanced apoptotic signalling, and reduced progenitor cell bioavailability, with consequent blunting of cardiovascular healing. Further research into the mechanisms that regulate the NO/ADMA balance may advance our understanding of cardiovascular diseases.


Asymmetric dimethylarginineCardiovascular healing


A recent article in this Journal by Ilhan et al. highlights the relation between raised plasma concentrations of asymmetric dimethylarginine (ADMA) and the presence of coronary artery disease explained, at least in part, by the coexistence of renal dysfunction [1]. Indeed, raised ADMA circulating levels were first described in patients with end-stage renal disease [2]. ADMA inhibits the synthesis of nitric oxide (NO) [1]. We propose that an abnormal NO/ADMA balance may have a role in hindering endogenous regenerative healing mechanisms, becoming a critical determinant of increased cardiovascular morbidity and mortality in ischemic patients with renal disease (Fig. 1).
Fig. 1

Cardiovascular homeostasis. Ischemic cardiovascular diseases may be viewed as an imbalance between cellular damage (e.g. determined by cardiovascular risk factors, raised ADMA, enhanced apoptosis, reduced nitric oxide) and regenerative processes

Production and metabolism

Asymmetric dimethylarginine (C8H18N4O2), a double methylated metabolite of the aminoacid arginine (Fig. 2), is an endogenous competitive inhibitor of all isoforms of nitric oxide synthase (NOS): neuronal (n)NOS I, inducible (i)NOS II and endothelial (e)NOS III. It competes with arginine for the NOS catalytic domain [3]. ADMA is produced in normal conditions by post-translational methylation of arginine residues within nuclear proteins. Nuclear protein methylation is mediated by specific protein N-methyltransferases (PRMTs) that produce several methylated arginine residues, including ADMA (Fig. 3). There are two major types of PRMTs. Type 1 PRMT generates monomethyl-l-arginine (l-NMMA) by methylating a nitrogen residue in the guanidine group of arginine; it also produces ADMA, through additional methylation of the same nitrogen residue. Type 2 PRMT methylates two different nitrogens of arginine, generating symmetric dimethylarginine (SDMA) (Fig. 2). The proteolysis of these methylated nuclear proteins by hydrolysis thus releases three arginine derivatives: ADMA, l-NMMA and SDMA, that move from the intracellular to the extracellular space using Y+ transporters for cationic aminoacids [3]. The plasma half-life of ADMA in healthy subjects is estimated to be 23.5 ± 6.8 min [4]. In the circulation, ADMA is largely bound to plasma proteins. Within tissues, it is mostly (>90%) metabolized by intracellular dimethylarginine dimethylaminohydrolase (DDAH). There are two types of this enzyme: DDAH I, which is highly expressed in the brain, kidney, pancreas, liver and skeletal muscle, and corresponds to the distribution of (n)NOS (NOS I); DDAH II is highly expressed in the heart, kidney and placenta, where (e)NOS (NOS III) is mainly present. These enzymes hydrolyse ADMA to form citrulline and dimethylamine. A minor quantity of ADMA is metabolized by other enzymes in the kidney and in the liver, or directly excreted in the urine [5]. The plasma concentrations of ADMA are considered to reflect intracellular levels [5]. The mean (SD) plasma concentrations of ADMA in young healthy subjects are reported to be 0.55 (0.14) μmol/l [6]. Different analytical assays (ELISA, high performance liquid chromatography, capillary electrophoresis and mass spectrometry) can be used to measure “free” endogenous ADMA concentrations in serum or plasma [6].
Fig. 2

Biochemical structure of ADMA. ADMA (C8H18N4O2) is a dimethylated form of l-arginine, where two methylic groups are covalently linked to the same aminoterminal nitrogen. l-NMMA (monomethyl-l-arginine) and SDMA (symmetric dimethylarginine) are two other l-arginine methylderivatives
Fig. 3

ADMA biosynthesis and function. ADMA is generated by type 1 protein methyltransferase (PRMT 1) and is metabolised by dimethylarginine dimethylaminohydrolase (DDAH). ADMA inhibits nitric oxide production competing with arginine for the catalytic domain of all forms of nitric oxide synthase (NOS). Kidney dysfunction, with reduced ADMA clearance and degradation, and ischemic necrosis, with increased protein nuclear proteolysis, contribute to higher ADMA blood concentrations


Elevated levels of ADMA may result from increased synthesis, reduced renal clearance, or reduced enzymatic degradation [7] (Fig. 3). In healthy men, more than 10 mg of ADMA are excreted in the urine over a 24 h period [7]. On the contrary, in patients with chronic renal failure, as a result of little or no urine output, ADMA is scarcely eliminated [2]. In patients with kidney dysfunction, degradation is also reduced [7]. As a consequence, ADMA plasma concentrations are two to six times higher in uremic patients than in healthy control subjects [8]. Through raised ADMA, kidney dysfunction may become an aggravating factor for patients with cardiovascular diseases [1] (Fig. 3). Indeed, kidney dysfunction is emerging as a strong predictor of death and recurrent cardiovascular events among patients with ischemic heart disease [9]. A rise in plasma ADMA levels may also contribute to the higher mortality of patients undergoing primary percutaneous coronary intervention who develop acute contrast induced nephropathy [9].

The reduced bioavailability of NO, typical of patients at high cardiovascular risk, may be explained—at least in part—by the detrimental effect of raised plasma ADMA concentrations on NO synthesis. Indeed, raised levels of ADMA are associated with all of the established metabolic and acquired cardiovascular risk factors: namely, hypertension, hypercholesterolemia, diabetes and smoking [10]. In uncomplicated type 1 diabetes mellitus, the plasma concentrations of ADMA increase (and the l-arginine/ADMA ratio decreases) even before the development of vascular complications [11]. Higher blood ADMA concentrations have been associated with carotid intimal–medial thickness [12]. Plasma concentrations of ADMA additionally correlate with those of homocysteine [1]. Homocysteine inhibits DDAH [13] and promotes the methylation of arginine residues [8] thus contributing in two ways to raise ADMA levels. Finally, nuclear protein methylation, and consequently ADMA production, is favoured by oxidative stress [3].

Summing up, cardiovascular risk factors, kidney dysfunction (with reduced ADMA clearance and degradation), and conditions causing cell damage (such as ischemic necrosis, with increased protein degradation) are associated with, and may contribute to, raised circulating levels of ADMA [1, 3]. Thus, as in a “vicious circle”, cardiovascular diseases may be both the cause and consequence of raised ADMA blood concentrations (Fig. 3). In this respect, ADMA is emerging as a powerful marker of cardiovascular risk.

ADMA and impaired cardiovascular healing

The homeostasis of the heart and blood vessels can be viewed as a balance between determinants of cardiovascular cell damage/death (determined for instance by cardiovascular risk factors, or toxic, ischemic, and autoimmune insults) and factors that promote the healing of cellular damage/death by regeneration (for instance, by available precursor cells, enhanced survival signals, reduced apoptosis) [14] (Figs. 1 and 3). Healing may occur through fibrosis (i.e. repair of tissue by poorly differentiated cells causing scarring and negative remodeling) or regeneration (i.e. renovated tissue by increasingly differentiated new cells derived from local or circulating progenitor cells) [15]. Reduced NO bioactivity not only promotes platelet aggregation, leucocyte adhesion, vasoconstriction, impaired glucose metabolism and free radical production, but also enhances vascular and cardiomyocyte apoptotic signalling [16] and hinders progenitor cell output [14]. Moreover, reduced systemic NO bioavailability is associated with decreased matrix metalloproteinase-9 (MMP-9) [15]. MMP-9 is required for progenitor cells mobilization and for endothelial and hematopoietic progenitor cell transfer from quiescent to proliferative niches within the bone marrow [15].

Low progenitor cell bioavailability in patients with ischemic heart disease has been associated with adverse outcomes [17]. These cells are able to proliferate and differentiate into mature elements, including hematopoietic, endothelial and muscle cells [18]. Their number is inversely related to the burden of cardiovascular risk factors [19]. Their bioavailability largely depends on the response of endogenous reservoirs (bone marrow or other tissues) to a combination of biosignals, including insulin like growth factor-1 and erythropoietin [14], that activate the intracellular Akt pathway and the biosynthesis of constitutive NO. Indeed, NO is an essential inducer of progenitor cell release [20]. Conversely, ADMA is emerging as a crucial suppressor of progenitor cell mobilization, differentiation and function [21]. In addition, the ADMA/DDAH balance is a critical regulator of endothelial cell motility [22]. Recent studies have shown that DDAH promotes endothelial repair after vascular injury [23]. Moreover, ADMA contributes to cell senescence, inducing apoptosis via the p38 mitogen-activated protein kinase (MAPK)/caspase-3-dependent signalling pathway in endothelial [16] and smooth muscle cells [24].


In the contemporary era of regenerative cardiovascular medicine, we propose that patients with ischemic heart disease, renal impairment, and high risk factor burden exhibit an increased risk of adverse cardiovascular outcomes, at least in part, through ADMA-mediated NO depression, enhanced apoptotic signalling, and low progenitor cell bioavailability, with an associated blunting of cardiovascular healing by regenerative mechanisms. We suggest that further research into the mechanisms that regulate the NO/ADMA balance may expand our understanding of cardiovascular diseases.

Copyright information

© Springer Science+Business Media, LLC 2007