Asymmetric dimethylarginine (ADMA) as an important risk factor for the increased cardiovascular diseases and heart failure in chronic kidney disease
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.
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2022, Biochimica et Biophysica Acta - General SubjectsCitation 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.
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These authors contribute equally to this work.