Toxic Dimethylarginines: Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA)
Abstract
:1. Introduction
2. Synthesis and Metabolism of ADMA and SDMA
2.1. Synthesis of ADMA and SDMA
2.2. Metabolism of ADMA and SDMA
2.3. Quantification of ADMA and SDMA
3. Clinical Conditions Associated with Elevated ADMA and SDMA Levels
3.1. ADMA and SDMA: From Uremic Toxins to CVD Risk Factors
3.2. Clinical Conditions Associated with Elevated ADMA Levels
3.3. Clinical Conditions Associated with Elevated SDMA Levels
3.4. Causal Link between the Plasma Levels of ADMA or SDMA and Clinical Outcome
4. Pathophysiology of ADMA and SDMA
4.1. ADMA and SDMA: Inhibition of NO Synthesis
4.2. Tissue ADMA and SDMA Concentrations
4.3. ADMA: Multifunctional Effects
4.4. SDMA: Pro-Inflammatory and Pro-Oxidant Properties
5. Potential Therapies for Reducing ADMA and SDMA Levels
6. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Patient Population | N | Correlation with Clinical Outcome | Year of First Report | Ref. |
---|---|---|---|---|
CKD/ESRD | >1500 | ND | 1992 | [3,46] |
Schizophrenia | 16 | ND | 1996 | [47] |
Childhood hypertension | 38 | ND | 1997 | [48] |
Peripheral arterial occlusive disease (PAOD) | 77 | ND | 1997 | [49] |
Hypercholesteremia | 49 | ND | 1998 | [50] |
Congestive heart failure | 84 | ADMA positively correlates with severity of heart failure | 1998 | [51] |
Preeclampsia | 12 | ND | 1998 | [52] |
Type 2 diabetes | 50 | ADMA correlates with brachial arterial dilation | 2000 | [53] |
Congenital heart disease (CHD) | 20 | Elevated ADMA in CHD with pulmonary hypertension | 2001 | [54] |
Stroke | 52 | ADMA correlates with homocysteine level | 2001 | [55] |
Hyperthyroidism | 19 | ADMA correlates with free T4 level | 2002 | [56] |
Critical illness in intensive care unit | 52 | ADMA increases risk for ICU death | 2003 | [57] |
Liver cirrhosis | 11 | ND | 2004 | [58] |
Type 1 diabetes | 408 | ADMA correlates with CVD events | 2004 | [59] |
Obesity | 563 | ND | 2004 | [60] |
Systemic lupus erythematous | 107 | ADMA correlates with CVD events | 2005 | [61] |
Idiopathic pulmonary arterial hypertension | 57 | ND | 2005 | [62] |
Hepatorenal syndrome | 11 | ND | 2006 | [63] |
Coronary artery disease | 145 | ADMA correlates with homocysteine level; ADMA negatively correlates with GFR | 2006 | [64] |
Prematurity | 19 | Elevated ADMA in male premature | 2006 | [65] |
Systemic sclerosis | 21 | Elevated ADMA in diffuse systemic sclerosis | 2006 | [66] |
Polycystic ovary syndrome (PCOS) | 106 | ND | 2008 | [67] |
Obstructive sleep apnea-hypopnea syndrome (OSAHS) | 34 | ND | 2008 | [68] |
Congenital urea cycle enzyme defects | 15 | Elevated ADMA in argininosuccinate synthase (ASS) deficiency and argininosuccinate lyase (ASL) deficiency | 2009 | [69] |
Rheumatiod arthritis (RA) | 25 | ND | 2009 | [70] |
Sickle cell disease (SCD) | 177 | ADMA correlates with mortality | 2009 | [71] |
Congenital portosystemic venous shunt (PSVS) | 14 | ND | 2010 | [72] |
Primary dysmenorrhea | 33 | ND | 2010 | [73] |
Inflammatory bowel diseases (IBD) | 63 | ADMA correlates with Crohn’s disease activity | 2010 | [74] |
Asthma | 17 | ND | 2011 | [75] |
Nonalcoholic fatty liver disease (NAFLD) | 35 | ND | 2011 | [76] |
Psoriatic arthritis | 22 | ADMA correlates with coronary flow reserve | 2011 | [77] |
Fibromyalgia | 27 | ND | 2011 | [78] |
Childhood acute lymphoblastic leukemia (ALL) | 25 | ND | 2012 | [79] |
Glaucoma | 210 | Elevated ADMA in advanced glaucoma | 2012 | [80] |
Pheochromocytoma | 18 | ND | 2013 | [81] |
Brucellosis | 39 | ND | 2014 | [82] |
Deep vein thrombosis (DVT) | 34 | ND | 2015 | [83] |
Short stature | 66 | ND | 2015 | [84] |
COPD | 58 | ND | 2015 | [85] |
Nocturia | 262 | ND | 2015 | [86] |
Neonatal sepsis | 31 | ADMA correlates with disease severity | 2015 | [87] |
Transient tachypnea of the newborn (TTN) | 36 | ND | 2016 | [88] |
Arginase 1 deficiency | 19 | ND | 2016 | [89] |
Idiopathic Parkinson’s disease (PD) | 82 | ND | 2016 | [90] |
Patient Population | N | Correlation with Clinical Outcome | Year of First Report | Ref. |
---|---|---|---|---|
CKD/ESRD | 10 | SDMA correlates with renal function | 1996 | [44,95] |
Childhood hypertension | 38 | SDMA correlates with GFR | 1997 | [48] |
Hyperthyroidism | 19 | ND | 2002 | [56] |
Critical illness in intensive care unit | 52 | SDMA correlates with creatinine level | 2003 | [57] |
Hepatorenal syndrome | 11 | ND | 2006 | [63] |
Coronary artery disease | 145 | SDMA negatively correlates with GFR | 2006 | [64] |
Type 2 diabetes mellitus (DM) | 103 | Elevated SDMA in type 2 DM with albuminuria | 2007 | [96] |
Alcoholic hepatitis | 52 | ND | 2007 | [97] |
Heart failure | 132 | ND | 2008 | [98] |
Preeclampsia | 47 | ND | 2009 | [99] |
Stroke | 394 | SDMA predicts all-cause mortality | 2010 | [100] |
Polycystic ovary syndrome (PCOS) | 16 | ND | 2011 | [101] |
Glaucoma | 210 | Elevated SDMA in advanced glaucoma | 2012 | [80] |
Hyperuricemia | 58 | SDMA correlates with uric acid level | 2013 | [102] |
Malaria | 123 | ND | 2014 | [103] |
Animal Models | Intervention | Protective Effects | Year of First Report | Ref. |
---|---|---|---|---|
LDL injection-induced endothelial dysfunction in rat | Probucol | Preserve endothelial function | 2002 | [129] |
LDL injection-induced endothelial dysfunction in rat | 17β-estradiol | Preserve endothelial function | 2004 | [130] |
Spontaneously hypertensive rat (SHR) | Pioglitazone | Increase renal DDAH-2 expression; Prevent hypertension | 2005 | [131] |
Zucker diabetic fatty rat | Farnesoid X receptor agonist | Increase hepatic DDAH-1 expression; Prevent atherosclerosis | 2006 | [132] |
LDL injection-induced endothelial dysfunction in rat | Taurine | Preserve endothelial function | 2007 | [133] |
Stress-induced preeclampsia in pregnant rat | l-arginine | Prevent hypertension and proteinuria | 2008 | [134] |
SHR | Rosuvastatin | Attenuate hypertension | 2008 | [135] |
STZ-induced diabetic rat | Telmisartan | Reduce renal PRMT-1 expression; Increase renal DDAH-1 expression | 2008 | [136] |
Ethanol-induced gastric mucosal injury in rat | Resveratrol analog BTM-0512 | Prevent gastric mucosa injury; Increase DDAH activity | 2010 | [137] |
Bile duct-ligated cirrhotic rat | Melatonin | Prevent liver damage; Increase DDAH activity | 2010 | [117] |
SHR | Melatonin | Prevent hypertension; Increase DDAH activity | 2010 | [138] |
SHR | Aliskiren | Prevent hypertension | 2011 | [139] |
SHR | Nebivolol | Prevent hypertension | 2011 | [140] |
Monocrotaline-induced pulmonary hypertension in rat | Rosuvastatin | Prevent pulmonary hypertension | 2011 | [141] |
Bile duct-ligated cirrhotic rat | Ornithine phenylacetate | Prevent liver damage | 2012 | [142] |
High-fat diet in rat | Atorvastatin | Improve endothelial function; Increase DDAH activity | 2012 | [143] |
5/6 nephrectomized rats | Shichimotsukokato | Prevent hypertension; Increase DDAH-2 level | 2012 | [144] |
Bile duct-ligated cirrhotic rat | Vitamin E | Improve endothelial function; Increase hepatic DDAH-2 level | 2012 | [145] |
Coronary artery-ligated rat | Salvianolic acid A | Improve cardiac damage; Increase DDAH activity | 2013 | [146] |
STZ-induced diabetic pregnant rat | l-citrulline | Prevent offspring hypertension; Increase renal DDAH-2 level | 2013 | [112] |
STZ-induced diabetic rat | Glucagon-like peptide-1 receptor agonist | Protect diabetic nephropathy; Reduce PRMT-1 expression | 2013 | [147] |
SHR | N-acetylcysteine | Prevent gastric mucosa injury; Increase DDAH activity | 2013 | [148] |
Prenatal dexamethasone exposure in rat | l-citrulline | Prevent offspring hypertension | 2014 | [149] |
SHR | l-citrulline | Prevent hypertension | 2014 | [150] |
SHR | Sodium nitrate | Prevent hypertension | 2014 | [150] |
High-fat and high-cholesterol diet in rat | Atorvastatin plus rosiglitazone | Protect endothelial function | 2014 | [151] |
Isoproterenol-induced heart failure in rat | Oxymatrine | Ameliorate ventricular function and hypertrophy; Increase DDAH-2 expression | 2014 | [152] |
Angiotensin II-induced hypertension in rat | Serelaxin | Attenuate hypertension and proteinuria | 2014 | [153] |
Lipopolysaccharide/D-galactosamine-induced liver injury | Metformin | Protect liver injury/Increase DDAH activity | 2014 | [154] |
SHR | Metformin | Prevent hypertension | 2014 | [110] |
Maternal caloric restriction.rat | Melatonin | Prevent offspring hypertension | 2014 | [155] |
Constriction of artery-induced subarachnoid hemorrhage in rat | 18β-glycyrrhetinic acid | Improve neurological outcome | 2015 | [156] |
Myocardial ischemia/reperfusion injury in rat | Apocynin | Protect myocardial injury | 2015 | [157] |
Maternal caloric restriction.rat | Aliskiren | Prevent offspring hypertension | 2015 | [158] |
High-fat and high-cholesterol diet in rat | Atorvastatin | Protective endothelial function | 2015 | [159] |
10% furctose administration rat | Fenofibrate | Reduce triglyceride level | 2015 | [160] |
Cyclosporine-induced nephrotoxicity | Nebivolol | Ameliorate endothelial function | 2016 | [161] |
l-NAME induced hypertension in rat | Novokinin | Prevent hypertension | 2016 | [162] |
Bile duct-ligated cirrhotic rat | Etanercept | Prevent brain damage | 2016 | [163] |
2016 | [164] | |||
STZ-induced cognitive impairment in rat | H2S releasing compounds ATB-346 and diallyl trisulfide | Ameliorate behavior performance | 2016 | [165] |
Aged rat | Epigallocatechin-3-gallate | Ameliorate erectile function; reduce PRMT-1 expression; Increase DDAH activity | 2016 | [166] |
Prenatal dexamethasone plus postnatal high-fat diet in rat | N-acetylcysteine | Prevent hypertension | 2016 | [167] |
Isoproterenol-induced heart failure in rat | Rosuvastatin | Ameliorate ventricular function and hypertrophy; Reduce PRMT-1 expression; Increase DDAH-2 expression | 2016 | [168] |
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Tain, Y.; Hsu, C. Toxic Dimethylarginines: Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA). Toxins 2017, 9, 92. https://doi.org/10.3390/toxins9030092
Tain Y, Hsu C. Toxic Dimethylarginines: Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA). Toxins. 2017; 9(3):92. https://doi.org/10.3390/toxins9030092
Chicago/Turabian StyleTain, You‐Lin, and Chien‐Ning Hsu. 2017. "Toxic Dimethylarginines: Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA)" Toxins 9, no. 3: 92. https://doi.org/10.3390/toxins9030092
APA StyleTain, Y., & Hsu, C. (2017). Toxic Dimethylarginines: Asymmetric Dimethylarginine (ADMA) and Symmetric Dimethylarginine (SDMA). Toxins, 9(3), 92. https://doi.org/10.3390/toxins9030092