Asymmetric dimethylarginine and impaired cardiovascular healing
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- Coluzzi, G., Santucci, E., Marzo, F. et al. J Thromb Thrombolysis (2009) 27: 168. doi:10.1007/s11239-007-0181-y
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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.
KeywordsAsymmetric dimethylarginineCardiovascular healing
Production and metabolism
Elevated levels of ADMA may result from increased synthesis, reduced renal clearance, or reduced enzymatic degradation  (Fig. 3). In healthy men, more than 10 mg of ADMA are excreted in the urine over a 24 h period . On the contrary, in patients with chronic renal failure, as a result of little or no urine output, ADMA is scarcely eliminated . In patients with kidney dysfunction, degradation is also reduced . As a consequence, ADMA plasma concentrations are two to six times higher in uremic patients than in healthy control subjects . Through raised ADMA, kidney dysfunction may become an aggravating factor for patients with cardiovascular diseases  (Fig. 3). Indeed, kidney dysfunction is emerging as a strong predictor of death and recurrent cardiovascular events among patients with ischemic heart disease . 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 .
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 . 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 . Higher blood ADMA concentrations have been associated with carotid intimal–medial thickness . Plasma concentrations of ADMA additionally correlate with those of homocysteine . Homocysteine inhibits DDAH  and promotes the methylation of arginine residues  thus contributing in two ways to raise ADMA levels. Finally, nuclear protein methylation, and consequently ADMA production, is favoured by oxidative stress .
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)  (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) . 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  and hinders progenitor cell output . Moreover, reduced systemic NO bioavailability is associated with decreased matrix metalloproteinase-9 (MMP-9) . 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 .
Low progenitor cell bioavailability in patients with ischemic heart disease has been associated with adverse outcomes . These cells are able to proliferate and differentiate into mature elements, including hematopoietic, endothelial and muscle cells . Their number is inversely related to the burden of cardiovascular risk factors . 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 , that activate the intracellular Akt pathway and the biosynthesis of constitutive NO. Indeed, NO is an essential inducer of progenitor cell release . Conversely, ADMA is emerging as a crucial suppressor of progenitor cell mobilization, differentiation and function . In addition, the ADMA/DDAH balance is a critical regulator of endothelial cell motility . Recent studies have shown that DDAH promotes endothelial repair after vascular injury . Moreover, ADMA contributes to cell senescence, inducing apoptosis via the p38 mitogen-activated protein kinase (MAPK)/caspase-3-dependent signalling pathway in endothelial  and smooth muscle cells .
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.