Elsevier

Nitric Oxide

Volume 78, 1 August 2018, Pages 113-120
Nitric Oxide

Asymmetric dimethylarginine (ADMA) as an important risk factor for the increased cardiovascular diseases and heart failure in chronic kidney disease

https://doi.org/10.1016/j.niox.2018.06.004Get rights and content

Highlights

  • Patients with chronic kidney disease have an increased cardiovascular morbidity and mortality.

  • ADMA is an endogenous inhibitors of nitric oxide synthases, and is an independent risk factor for cardiovascular diseases.

  • Chronic kidney disease causes profound increase of systemic ADMA that attenuates NO production.

  • Increased cardiovascular morbidity in chronic kidney disease may relate to the dramatic increase of systemic ADMA and L-NMMA.

Abstract

Patients with chronic kidney disease have an increased cardiovascular morbidity and mortality. It has been recognized that the traditional cardiovascular risk factors could only partially explain the increased cardiovascular morbidity and mortality in patients with chronic kidney disease. Asymmetric dimethylarginine (ADMA) and N-monomethy l-arginine (L-NMMA) are endogenous inhibitors of nitric oxide synthases that attenuate nitric oxide production and enhance reactive oxidative specie generation. Increased plasma ADMA and/or L-NMMA are strong and independent risk factor for chronic kidney disease, and various cardiovascular diseases such as hypertension, coronary artery disease, atherosclerosis, diabetes, and heart failure. Both ADMA and L-NMMA are also eliminated from the body through either degradation by dimethylarginine dimethylaminohydrolase-1 (DDAH1) or urine excretion. This short review will exam the literature of ADMA and L-NMMA degradation and urine excretion, and the role of chronic kidney diseases in ADMA and L-NMMA accumulation and the increased cardiovascular disease risk. Based on all available data, it appears that the increased cardiovascular morbidity in chronic kidney disease may relate to the dramatic increase of systemic ADMA and L-NMMA after kidney failure.

Introduction

Chronic kidney disease (CKD) is generally described as the presence of kidney damage and reduced kidney function over 3 months. Cardiovascular diseases (CVD) are the leading cause of death in North America [28,32,37], and patents with CKD show an increase of prevalence of CVD such as hypertension, peripheral vascular disease, and congestive heart failure (CHF) [40,67,71]. In addition, the cardiovascular morbidity and mortality are markedly increased in patients with CKD [67,71]. It is reported that up 25–47% patients are with CVD such as the CHF, ischemia cardiomyopathy, or ventricular hypertrophy in patients with severe CKD [40,67,71]. However, the mechanism of the increased cardiovascular risk in CKD is not very clear.

Asymmetric dimethylarginine (ADMA) and N-monomethy l-arginine (L-NMMA) are endogenous nitric oxide synthase inhibitors. ADMA and/or L-NMMA are recognized as a strong and independent risk factor(s) for various cardiovascular diseases such as hypertension, coronary artery disease, atherosclerosis, pulmonary hypertension, atrial fibrillation, stroke, peripheral vascular diseases, diabetes and CHF [[2], [3], [4],8,15,55,76,94]. ADMA and L-NMMA attenuate nitric oxide (NO) production by inhibition of nitric oxide synthase (NOS) activity [[10], [11], [12],41,62] (Fig. 1). ADMA and L-NMMA also enhance NOS uncoupling to produce reactive oxidative species (ROS) such as superoxide anion (O2) and peroxynitrite (ONOO), which could further reduce the cardiovascular NO bioavailability. ADMA and L-NMMA are eliminated from the body by either DDAH1 degradation [58,61] or renal excretion [1,47]. Unlike other cardiovascular disease conditions, CKD often causes a dramatic increase of circulating ADMA and/or L-NMMA [48,59,63,66,92,93]. Here we will briefly review the major findings regarding ADMA and L-NMMA metabolism, their renal elimination, their effect on NO bioavailability and ROS production, and their important roles in promoting cardiovascular diseases. Based on the dramatic increase of circulating ADMA and/or L-NMMA in CKD patients [48,59,63,66,93], and the role of ADMA and L-NMMA in promoting cardiovascular diseases [[2], [3], [4],8,54,73,74], the dramatic elevation of plasma ADMA and L-NMMA levels might be the major culprits for the increased cardiovascular morbidity and mortality in patients with CKD (Fig. 2).

Section snippets

Basic role and mechanism of NO in regulating cardiovascular function

NO plays an important role in regulating various cardiovascular function [14,38,46]. NO is produced by NOS by using l-arginine as a substrate. There are 3 well-recognized enzymes for NO production are neuronal nitric oxide synthase (nNOS or NOS1) and inducible nitric oxide synthase (iNOS or NOS2), and endothelial nitric oxide synthase (eNOS or NOS3) [14,38,39] (Fig. 1). eNOS is mainly expressed in vascular endothelial cells, while nNOS is mainly expressed in neuronal cells. Since both eNOS and

ADMA and L-NMMA production, transportation and elimination

Protein methylation plays an important role in many cellular functions and occurs constitutively in various cells under both normal control conditions or after stresses. The production of ADMA and L-NMMA is the result of proteolysis of proteins containing methylated arginines [57,65,72]. L-NMMA is formed when protein-incorporated l-arginine is methylated by the enzymes protein arginine methyltransferases type-I (PRMT-I) or type-II (PRMT-II) [57,65]. PRMT-I can further methylate L-NMMA,

ADMA and L-NMMA attenuate NO-cGMP-PKG signaling and cardiovascular endothelial function

ADMA and L-NMMA regulate cardiovascular function through attenuating NO production and increase NOS-derived superoxide anion production (Figs. 1 and 2). As ADMA is more abundant than L-NMMA, most of the studies have focused on the physiological or pathological effects of ADMA in various biological or clinical conditions. ADMA and L-NMMA not only attenuate NO production, but also promote NOS-derived superoxide anion production [13,89,90]. The superoxide anion can further bind NO to generate

Effect of ADMA and L-NMMA on NOS uncoupling

Studies have also demonstrated that endogenous NOS inhibitors ADMA and L-NMMA can also enhance NOS-derived O2 production and ONOO production through a process called NOS uncoupling (Fig. 1). NOS uncoupling generally occurs when NOS is exposed to oxidant stress (including peroxynitrite), when it is deficient of cofactor BH4 [22,49], or when it is deprived of its substrate l-arginine [90]. Since BH4 stabilizes the dimeric forms of eNOS, nNOS and iNOS [6,23], oxidation of BH4 to BH2, or BH4

Effect of ADMA and/or L-NMMA on cardiovascular diseases

ADMA and/or L-NMMA accumulation also occurs in hypertension [74], atherosclerosis [43,73], cardiac valve disease [2], idiopathic cardiomyopathy [3], renal failure [44], diabetes [4,54], aging, atrial fibrillation, and CHF [27,81] [15,16], a group of diseases cause CHF (Fig. 2). Elevated plasma ADMA and/or L-NMMA level is associated with an increased risk for developing angina pectoris, myocardial infarction or cardiac death [9,10]. Plasma ADMA and/or L-NMMA level is a strong and independent

The essential role of DDAH1 in degrading ADMA and L-NMMA

As ADMA was first isolated from human urine by Kakimoto and Akazawa in 1970 [47], renal excretion was initially recognized as the major route for ADMA elimination in human subjects. However, a study from McDermott subsequently showed that the urinary recoveries of L-NMMA and ADMA following intravenous injection in normal rabbits were 0.14% and 5.1%, respectively, indicating that both L-NMMA and ADMA undergo extensive metabolism in healthy animals [58]. It was then reported that less than 17% of

Alteration of systemic ADMA in CKD suggests an important role of kidneys in ADMA metabolism

While two previous studies demonstrated that only small amount of ADMA and/or L-NMMA are eliminated through urine excretion in normal human subject and experimental animals [1,58], enormous evidences obtained from renal failure patients indicate that kidneys might exert an important role in elimination of ADMA and L-NMMA in clinical conditions. Thus, several studies showed that plasma ADMA and L-NMMA generally increases over 4 fold (even increased up to 10 fold in some reports) in patients with

ADMA alteration in CKD experimental animal models

While the clinic studies clearly show that severe CKD causes a dramatic increase of plasma ADMA contents, various experimental animal models of CKD have so far failed to recapitulate the apparent elevation of plasma ADMA observed in CKD patients. For examples, the commonly used 1/2 or 5/6 nephrectomized wild type mice or rats only caused moderate increases of plasma ADMA in mice or rats [43,64,77], suggest a better experimental animal model(s) is needed to test the causal role of chronic

The mechanism of ADMA and/or L-NMMA accumulation in cardiovascular diseases

Although the detailed mechanism for increased ADMA and L-NMMA in cardiovascular diseases is not totally clear, in principle, the overall ADMA elevation can be a result for 3 scenario such as (i) an increased ADMA and L-NMMA production in response to stresses or increased degradation or turnover of proteins containing methylated arginine [65,72]; (ii) a decreased ADMA and L-NMMA degradation by DDAH1 dysfunction; or (iii) a reduced ADMA and L-NMMA excretion by kidney dysfunction [44,48,59,66,93].

Potential therapeutic targets or therapies to reduce ADMA

Since ADMA and L-NMMA are recognized risk factors for cardiovascular disease through attenuating vascular NO/cGMP signaling, effects have been undertaken to reduce ADMA and L-NMMA. As protein methylation plays an important role in many cellular functions and occurs constitutively in various cells under both normal or pathological conditions, reduction of ADMA and L-NMMA production is generally regarded as an unattractive approach. Thus, most of the effort in the ADMA field is to identify

Summary

Cardiovascular diseases such as (hypertension, heart failure, and coronary artery disease) are generally associated mild or less than 20% increase of plasma ADMA and/or L-NMMA, and increased plasma ADMA and/or L-NMMA is a strong and independent risker factor for many cardiovascular diseases. Increased ADMA and/or L-NMMA can cause detrimental effects on vascular endothelial cell growth, abnormal angiogenesis and vessel injury repair through attenuating NO production or increase of ROS

Sources of funding

This study was supported by Grants HL098669, HL102597, R01HL105406 from the National Institutes of Health, and a grant in aid from American Heart Association. The study was also supported by the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning to Dr. Xu.

Disclosures

None.

Acknowledgements

None.

References (98)

  • E.M. Jeong et al.

    Tetrahydrobiopterin improves diastolic dysfunction by reversing changes in myofilament properties

    J. Mol. Cell. Cardiol.

    (2013)
  • Y. Kakimoto et al.

    Isolation and identification of N-G,N-G- and N-G,N'-G-dimethyl-arginine, N-epsilon-mono-, di-, and trimethyllysine, and glucosylgalactosyl- and galactosyl-delta-hydroxylysine from human urine

    J. Biol. Chem.

    (1970)
  • W. Li et al.

    Premature death and age-related cardiac dysfunction in male eNOS-knockout mice

    J. Mol. Cell. Cardiol.

    (2004)
  • X. Liu et al.

    Effect of asymmetric dimethylarginine (ADMA) on heart failure development

    Nitric Oxide

    (2016)
  • A.E. McBride et al.

    State of the arg: protein methylation at arginine comes of age

    Cell

    (2001)
  • T. Ogawa et al.

    Occurrence of a new enzyme catalyzing the direct conversion of NG,NG-dimethyl-L-arginine to L-citrulline in rats

    Biochem. Biophys. Res. Commun.

    (1987)
  • A.J. Pope et al.

    Role of the PRMT-DDAH-ADMA axis in the regulation of endothelial nitric oxide production

    Pharmacol. Res.

    (2009)
  • D.S. Raj et al.

    Hemodynamic changes during hemodialysis: role of nitric oxide and endothelin

    Kidney Int.

    (2002)
  • R.N. Rodionov et al.

    Human alanine-glyoxylate aminotransferase 2 lowers asymmetric dimethylarginine and protects from inhibition of nitric oxide production

    J. Biol. Chem.

    (2010)
  • R. Shah et al.

    CRIC study investigators. Serum fractalkine (CX3CL1) and cardiovascular outcomes and diabetes: findings from the chronic renal insufficiency cohort (CRIC) study

    Am. J. Kidney Dis.

    (2015)
  • C.T. Tran et al.

    Chromosomal localization, gene structure, and expression pattern of DDAH1: comparison with DDAH2 and implications for evolutionary origins

    Genomics

    (2000)
  • S. vonHaehling et al.

    Ursodeoxycholic acid in patients with chronic heart failure: a double-blind, randomized, placebo-controlled, crossover trial

    J. Am. Coll. Cardiol.

    (2012)
  • X. Wang et al.

    Proteasomal and lysosomal protein degradation and heart disease

    J. Mol. Cell. Cardiol.

    (2014)
  • Y. Wang et al.

    S-nitrosylation of PDE5 increases its ubiquitin-proteasomal degradation

    Free Radic. Biol. Med.

    (2015)
  • M.I. Yilmaz et al.

    The determinants of endothelial dysfunction in CKD: oxidative stress and asymmetric dimethylarginine

    Am. J. Kidney Dis.

    (2006)
  • V. Achan et al.

    Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase

    Arterioscler. Thromb. Vasc. Biol.

    (2003)
  • O.A. Ali et al.

    Interactions between inflammatory activation and endothelial dysfunction selectively modulate valve disease progression in patients with bicuspid aortic valve

    Heart

    (2014)
  • M. Anderssohn et al.

    Asymmetric dimethylarginine as a mediator of vascular dysfunction and a marker of cardiovascular disease and mortality: an intriguing interaction with diabetes mellitus

    Diabetes Vasc. Dis. Res.

    (2010)
  • F.I. Arrigoni et al.

    Metabolism of asymmetric dimethylarginines is regulated in the lung developmentally and with pulmonary hypertension induced by hypobaric hypoxia

    Circulation

    (2003)
  • L.A. Barouch et al.

    Nitric oxide regulates the heart by spatial confinement of nitric oxide synthase isoforms

    Nature

    (2002)
  • R.H. Böger et al.

    Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community

    Circulation

    (2009)
  • R.H. Böger

    Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the "L-arginine paradox" and acts as a novel cardiovascular risk factor

    J. Nutr.

    (2004)
  • D.E. Burger et al.

    Neuronal nitric oxide synthase protects against myocardial infarction-induced ventricular arrhythmia and mortality in mice

    Circulation

    (2009)
  • R. Carnicer et al.

    Nitric oxide synthases in heart failure

    Antioxidants Redox Signal.

    (2013)
  • A. Cengel et al.

    Asymmetrical dimethylarginine level in atrial fibrillation

    Acta Cardiol.

    (2008)
  • Y. Chen et al.

    Left ventricular failure produces profound lung remodeling and pulmonary hypertension in mice: heart failure causes severe lung disease

    Hypertension

    (2012)
  • Y. Chen et al.

    Dimethylarginine dimethylaminohydrolase and endothelial dysfunction in failing hearts

    Am. J. Physiol. Heart Circ. Physiol.

    (2005)
  • Y. Chen et al.

    Alterations of gene expression in failing myocardium following left ventricular assist device support

    Physiol. Genom.

    (2003)
  • Y. Chen et al.

    Nitric oxide modulates myocardial oxygen consumption in the failing heart

    Circulation

    (2002)
  • Y. Chen et al.

    Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure

    Am. J. Physiol. Heart Circ. Physiol.

    (2003)
  • F. Cosentino et al.

    Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensiverats

    J. Clin. Invest.

    (1998)
  • B.R. Crane et al.

    Structure of nitric oxide synthase oxygenase dimer with pterin and substrate

    Science

    (1998)
  • A. Dasgupta et al.

    Soluble guanylate cyclase: a new therapeutic target for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

    Clin. Pharmacol. Ther.

    (2015)
  • H. Dayoub et al.

    Dimethylargininedimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence

    Circulation

    (2003)
  • L. Dowsett et al.

    Endothelial DDAH1 is an important regulator of angiogenesis but does not regulate vascular reactivity or hemodynamic homeostasis

    Circulation

    (2015)
  • C. Dückelmann et al.

    Asymmetric dimethylarginine enhances cardiovascular risk prediction in patients with chronic heart failure

    Arterioscler. Thromb. Vasc. Biol.

    (2007)
  • L.L. Emanuel et al.

    Care of patients with end-stage heart disease

  • R. Feil et al.

    Cyclic GMP-dependent protein kinases and the cardiovascular system: insights from genetically modified mice

    Circ. Res.

    (2003)
  • M. Gheorghiade et al.

    Soluble guanylate cyclase: a potential therapeutic target for heart failure

    Heart Fail. Rev.

    (2013)
  • Cited by (86)

    • Esomeprazole covalently interacts with the cardiovascular enzyme dimethylarginine dimethylaminohydrolase: Insights into the cardiovascular risk of proton pump inhibitors

      2022, Biochimica et Biophysica Acta - General Subjects
      Citation Excerpt :

      However, no unifying mechanisms have been identified for the potentially harmful effects of PPIs. ADMA is a risk factor for cognitive impairment, progression of chronic kidney disease (CKD), vascular dysfunction, and cardiovascular mortality [13,34,35]. As an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), elevated levels of ADMA diminishes the production of nitric oxide (NO) to promote vasoconstriction and impair blood flow to vital tissues including the brain, kidney, and heart.

    View all citing articles on Scopus
    1

    These authors contribute equally to this work.

    View full text