Many cardiovascular diseases and drug-induced complications are associated with - or even based on - an imbalance betweenthe formation of reactive oxygen and nitrogen species (RONS) and antioxidant enzymes catalyzing the break-down of these harmful oxidants.According to the “kindling radical” hypothesis, the formation of RONS may trigger in certain conditions the activation of additionalsources of RONS. According to recent reports, vascular dysfunction in general and cardiovascular complications such as hypertension,atherosclerosis and coronary artery diseases may be connected to inflammatory processes. The present review is focusing on the uncouplingof endothelial nitric oxide synthase (eNOS) by different mechanisms involving so-called “redox switches”. The oxidative depletionof tetrahydrobiopterin (BH 4 ), oxidative disruption of the dimeric eNOS complex, S-glutathionylation and adverse phosphorylation aswell as RONS-triggered increases in levels of asymmetric dimethylarginine (ADMA) will be discussed. But also new concepts of eNOSuncoupling and state of the art detection of this process will be described. Another part of this review article will address pharmaceuticalinterventions preventing or reversing eNOS uncoupling and thereby normalize vascular function in a given disease setting. We finallyturn our attention to the inflammatory mechanisms that are also involved in the development of endothelial dysfunction and cardiovasculardisease. Inflammatory cell and cytokine profiles as well as their interactions, which are among the kindling mechanisms for the developmentof vascular dysfunction will be discussed on the basis of the current literature.

eNOS Uncoupling in Cardiovascular Diseases - the Role of Oxidative Stress and Inflammation

Asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA) are endogenously produced amino acids that inhibit all three isoforms of nitric oxide synthase (NOS). ADMA accumulates in various disease states, including renal failure, diabetes and pulmonary hypertension, and its concentration in plasma is strongly predictive of premature cardiovascular disease and death. Both L-NMMA and ADMA are eliminated largely through active metabolism by dimethylarginine dimethylaminohydrolase (DDAH) and thus DDAH dysfunction may be a crucial unifying feature of increased cardiovascular risk. However, despite considerable interest in this pathway and in the role of ADMA as a cardiovascular risk factor, there is little evidence to support a causal role of ADMA in pathophysiology. Here we reveal the structure of human DDAH-1 and probe the function of DDAH-1 both by deleting the DDAH1 gene in mice and by using DDAH-specific inhibitors which, as we demonstrate by crystallography, bind to the active site of human DDAH-1. We show that loss of DDAH-1 activity leads to accumulation of ADMA and reduction in NO signaling. This in turn causes vascular pathophysiology, including endothelial dysfunction, increased systemic vascular resistance and elevated systemic and pulmonary blood pressure. Our results also suggest that DDAH inhibition could be harnessed therapeutically to reduce the vascular collapse associated with sepsis.

Disruption of methylarginine metabolism impairs vascular homeostasis.

Arginine (L-arginine), is an amino acid involved in a number of biological processes, including the biosynthesis of proteins, host immune response, urea cycle, and nitric oxide production. In this systematic review, we focus on the functional role of arginine in the regulation of endothelial function and vascular tone. Both clinical and preclinical studies are examined, analyzing the effects of arginine supplementation in hypertension, ischemic heart disease, aging, peripheral artery disease, and diabetes mellitus.

https://www.mdpi.com/2227-9059/8/8/277/pdf

Arginine and Endothelial Function

Background 
A growing number of studies linked elevated concentrations of circulating asymmetric (ADMA) and symmetric (SDMA) dimethylarginine to mortality and cardiovascular disease (CVD) events. To summarize the evidence, we conducted a systematic review and quantified associations of ADMA and SDMA with the risks of all-cause mortality and incident CVD in meta-analyses accounting for different populations and methodological approaches of the studies.


Methods 
Relevant studies were identified in PubMed until February 2015. We used random effect models to obtain summary relative risks (RR) and 95% confidence intervals (95%CIs), comparing top versus bottom tertiles. Dose-response relations were assessed by restricted cubic spline regression models and potential non-linearity was evaluated using a likelihood ratio test. Heterogeneity between subgroups was assessed by meta-regression analysis.


Results 
For ADMA, 34 studies (total n = 32,428) investigating associations with all-cause mortality (events = 5,035) and 30 studies (total n = 30,624) investigating the association with incident CVD (events = 3,396) were included. The summary RRs (95%CI) for all-cause mortality were 1.52 (1.37–1.68) and for CVD 1.33 (1.22–1.45), comparing high versus low ADMA concentrations. Slight differences were observed across study populations and methodological approaches, with the strongest association of ADMA being reported with all-cause mortality in critically ill patients. For SDMA, 17 studies (total n = 18,163) were included for all-cause mortality (events = 2,903), and 13 studies (total n = 16,807) for CVD (events = 1,534). High vs. low levels of SDMA, were associated with increased risk of all-cause mortality [summary RR (95%CI): 1.31 (1.18–1.46)] and CVD [summary RR (95%CI): 1.36 (1.10–1.68) Strongest associations were observed in general population samples.


Conclusions 
The dimethylarginines ADMA and SDMA are independent risk markers for all-cause mortality and CVD across different populations and methodological approaches.

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0165811&type=printable

Asymmetric and Symmetric Dimethylarginine as Risk Markers for Total Mortality and Cardiovascular Outcomes: A Systematic Review and Meta-Analysis of Prospective Studies.

Objective— Plasma levels of an endogenous nitric oxide (NO) synthase inhibitor, asymmetric dimethylarginine (ADMA), are elevated in chronic renal failure, hypertension, and chronic heart failure. In patients with renal failure, plasma ADMA levels are an independent correlate of left ventricular ejection fraction. However, the cardiovascular effects of a systemic increase in ADMA in humans are not known. Methods and Results— In a randomized, double-blind, placebo-controlled study in 12 healthy male volunteers, we compared the effects of intravenous low-dose ADMA and placebo on heart rate, blood pressure, cardiac output, and systemic vascular resistance at rest and during exercise. We also tested the hypothesis that ADMA is metabolized in humans in vivo by dimethylarginine dimethylaminohydrolase (DDAH) enzymes. Low-dose ADMA reduced heart rate by 9.2±1.4% from 58.9±2.0 bpm (P<0.001) and cardiac output by 14.8±1.2% from 4.4±0.3 L/min (P<0.001). ADMA also increased mean blood pressure by 6.0±1.2% from 88.6±3....

Asymmetric Dimethylarginine Causes Hypertension and Cardiac Dysfunction in Humans and Is Actively Metabolized by Dimethylarginine Dimethylaminohydrolase

Interaction of the cardiovascular risk marker asymmetric dimethylarginine (ADMA) with the human cationic amino acid transporter 1 (CAT1)

Asymmetric dimethylarginine (ADMA), inhibiting the nitric oxide (NO) synthesis from l-arginine, is a known cardiovascular risk factor. Our aim was to investigate if ADMA and/or l-arginine are substrates of the human cationic amino acid transporters 2A (CAT2A, SLC7A2A) and 2B (CAT2B, SLC7A2B), the organic cation transporter 2 (OCT2, SLC22A2), and the multidrug and toxin extrusion protein 1 (MATE1, SLC47A1). We systematically investigated the kinetics of ADMA and l-arginine transport in human embryonic kidney (HEK293) cells stably overexpressing CAT2A, CAT2B, OCT2, or MATE1. Vector-only transfected HEK293 cells served as controls. Compared to vector control cells, uptake of ADMA and l-arginine was significantly higher (p < 0.05) in cells expressing CAT2B and OCT2 at almost all investigated concentrations, while cells expressing CAT2A only showed a significant uptake at concentrations above 300 μM. Uptake of MATE1 overexpressing cells was significantly (p < 0.05) higher at pH 7.8 and 8.2 than controls. Apparent V
 max values (nmol mg protein−1 min−1) for cellular uptake of ADMA and l-arginine were ≈11.8 ± 1.2 and 19.5 ± 0.7 for CAT2A, ≈14.3 ± 1.0 and 15.3 ± 0.4 for CAT2B, and 6.3 ± 0.3 and >50 for OCT2, respectively. Apparent K
 m values (μmol/l) for cellular uptake of ADMA and l-arginine were ≈3,033 ± 675 and 3,510 ± 419 for CAT2A, ≈4,021 ± 532 and 952 ± 92 for CAT2B, and 967 ± 143 and >10,000 for OCT2, respectively. ADMA and l-arginine are substrates of human CAT2A, CAT2B, OCT2 and MATE1. Transport kinetics of CAT2A, CAT2B, and OCT2 indicate a low affinity, high capacity transport, which may be relevant for renal and hepatic elimination of ADMA or l-arginine.

Transport of asymmetric dimethylarginine (ADMA) by cationic amino acid transporter 2 (CAT2), organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1).

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Interaction of the cardiovascular risk marker asymmetric dimethylarginine (ADMA) with the human cationic amino acid transporter 1 (CAT1)

Transport of asymmetric dimethylarginine (ADMA) by cationic amino acid transporter 2 (CAT2), organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1).