Regulation | Transcriptional and Post-translational Regulation of the Dimethylarginines ADMA and SDMA and Their Impact on the L-arginine – Nitric Oxide Pathway

Hannemann, Juliane; Böger, Rainer H.

doi:10.1016/b978-0-12-819460-7.00128-6

Cited by 5 publications

(8 citation statements)

References 148 publications

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“…In the present study, we aimed to evaluate the role of NO alterations in fetal programming of hypertension induced by maternal undernutrition during gestation, which we have previously demonstrated in adult male offspring [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34],…”

Section: Discussionmentioning

confidence: 99%

“…Although l-Arg/ADMA ratio was not different between groups, ADMA and SMDA were elevated in 21-day-old MUN offspring. ADMA and SDMA are released from tissues during physiological turnover of di-methylated proteins [21]. ADMA is enzymatically inactivated by dimethylarginine dimethylaminohydrolase (DDAH) [22] whilst SDMA is cleared by the kidneys.…”

Section: Discussionmentioning

confidence: 99%

“…It was previously reported that dysfunction of the placental ADMA metabolism by DDAH contributes to high ADMA concentration in the late phase of pregnancy and may be one common cause of preeclampsia and FGR [2,9]. Dysfunction of DDAH may be caused by genetic polymorphisms [22] or by oxidative inactivation of the enzyme [21]. It is possible that the higher ADMA levels observed at weaning could be related to oxidative inactivation of DDAH, as we have previously demonstrated a lower degree of antioxidants in MUN rats at this age, particularly in males [33].…”

Section: Discussionmentioning

confidence: 99%

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Vascular nitrosative stress in hypertension induced by fetal undernutrition in rats

et al. 2023

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Fetal undernutrition predisposes to hypertension development. Since nitric oxide (NO) is a key factor in blood pressure control, we aimed to investigate the role of NO alterations in hypertension induced by fetal undernutrition in rats. Male and female offspring from dams exposed to undernutrition during the second half of gestation (MUN) were studied at 21 days (normotensive) and 6 months of age (hypertension developed only in males). In aorta, we analyzed total and phosphorylated endothelial NO synthase (eNOS, p-eNOS), 3-nitrotyrosine (3-NT), and Nrf2 (Western blot). In plasma we assessed l-arginine, asymmetric and symmetric dimethylarginine (ADMA, SDMA; LC–MS/MS), nitrates (NOx, Griess reaction), carbonyl groups, and lipid peroxidation (spectrophotometry). In iliac arteries, we studied superoxide anion production (DHE staining, confocal microscopy) and vasodilatation to acetylcholine (isometric tension). Twenty-one-day-old MUN offspring did not show alterations in vascular e-NOS or 3NT expression, plasma l-Arg/ADMA ratio, or NOx. Compared to control group, 6-month-old MUN rats showed increased aortic expression of p-eNOS/eNOS and 3-NT, being Nrf2 expression lower, elevated plasma l-arginine/ADMA, NOx and carbonyl levels, increased iliac artery DHE staining and reduced acetylcholine-mediated relaxations. These alterations in MUN rats were sex-dependent, affecting males. However, females showed some signs of endothelial dysfunction. We conclude that increased NO production in the context of a pro-oxidative environment, leads to vascular nitrosative damage and dysfunction, which can participate in hypertension development in MUN males. Females show a better adaptation, but signs of endothelial dysfunction, which can explain hypertension in ageing.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Vascular nitrosative stress in hypertension induced by fetal undernutrition in rats

et al. 2023

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“…Another dimethylarginine, symmetric dimethylarginine (SDMA), is unable to directly interfere with NOS activity, but like ADMA, it may inhibit CAT-2, the cellular uptake transporter for L-arginine ( 145 , 146 ). We have recently reviewed in detail the transcriptional and post-translational mechanisms of regulation of dimethylarginine metabolism ( 9 ). Dimethylation of proteins occurs as a process of posttranslational protein modification and leads to increased hydrophobicity of the respective protein moieties.…”

Section: Dysregulation Of the Endothelial No Pathway In The Hypoxic P...mentioning

confidence: 99%

“…The generation of NO, which occurs mainly in the vascular endothelium, is regulated (a) by transcriptional and posttranscriptional mechanisms affecting the NO-producing enzyme, endothelial nitric oxide synthase (eNOS), (b) by factors regulating the enzymatic activity of eNOS, and (c) by reactive oxygen species that rapidly react—and thereby inactivate—NO once released from the endothelium. The enzymatic activity of eNOS is also regulated by the presence of methylarginines ( 9 ). Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of eNOS; elevated ADMA concentration has been shown to lead to impaired NO generation and endothelial dysfunction which is reversible by L-arginine ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of the Nitric Oxide/Dimethylarginine Pathway in Hypoxic Pulmonary Vasoconstriction—Molecular Mechanisms and Clinical Significance

Hannemann

Böger

2022

Front. Med.

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The pulmonary circulation responds to hypoxia with vasoconstriction, a mechanism that helps to adapt to short-lived hypoxic episodes. When sustained, hypoxic pulmonary vasoconstriction (HPV) may become deleterious, causing right ventricular hypertrophy and failure, and contributing to morbidity and mortality in the late stages of several chronic pulmonary diseases. Nitric oxide (NO) is an important endothelial vasodilator. Its release is regulated, amongst other mechanisms, by the presence of endogenous inhibitors like asymmetric dimethylarginine (ADMA). Evidence has accumulated in recent years that elevated ADMA may be implicated in the pathogenesis of HPV and in its clinical sequelae, like pulmonary arterial hypertension (PAH). PAH is one phenotypic trait in experimental models with disrupted ADMA metabolism. In high altitude, elevation of ADMA occurs during long-term exposure to chronic or chronic intermittent hypobaric hypoxia; ADMA is significantly associated with high altitude pulmonary hypertension. High ADMA concentration was also reported in patients with chronic obstructive lung disease, obstructive sleep apnoea syndrome, and overlap syndrome, suggesting a pathophysiological role for ADMA-mediated impairment of endothelium-dependent, NO-mediated pulmonary vasodilation in these clinically relevant conditions. Improved understanding of the molecular (dys-)regulation of pathways controlling ADMA concentration may help to dissect the pathophysiology and find novel therapeutic options for these diseases.

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Symmetric Dimethylarginine Predicts Previously Undetected Atrial Fibrillation in Patients With Ischemic Stroke

Hannemann,

Wasser,

Mileva

et al. 2024

JAHA

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Background Atrial fibrillation (AF) is a stroke risk factor that often remains undetected at hospital admission. Long‐term Holter monitoring helps to identify patients with previously unrecognized AF. Asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are elevated in AF in cross‐sectional studies. We analyzed ADMA, SDMA, and other L‐arginine metabolites to assess their association with AF in the Find‐AF trial. Methods and Results We included 280 patients presenting with acute cerebral ischemia. Patients presenting in sinus rhythm received 7‐day Holter‐ECG. Biomarkers were quantified by ultra‐performance liquid chromatography–tandem mass spectrometry. We also analyzed protein methylation and L‐arginine‐related metabolites in human induced pluripotent stem cell‐derived cardiomyocytes in vitro. ADMA and SDMA were elevated in 44 patients who presented with AF. SDMA, but not ADMA, was significantly elevated in patients newly diagnosed with AF in Holter‐ECG as compared with those in sinus rhythm. SDMA plasma concentration >0.571 μmol/L significantly predicted presence of AF in Holter‐ECG (area under the curve=0.676 [0.530–0.822]; P =0.029; sensitivity 0.786, specificity 0.572). SDMA levels further increased in patients with AF during the first 24 hours in hospital, and ADMA levels remained stable. In vitro, induced pluripotent stem cell‐derived cardiomyocytes showed increased symmetric protein methylation and elevated SDMA during rapid pacing (2.0 Hz versus 0.5 Hz), whereas asymmetric protein methylation and ADMA were unchanged. Conclusions SDMA at admission was significantly elevated in stroke patients presenting with AF and showed a moderate but significant prospective association with previously unrecognized AF. Thus, stroke patients with elevated SDMA concentration at admission may specifically benefit from extended Holter‐ECG monitoring.

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Regulation | Transcriptional and Post-translational Regulation of the Dimethylarginines ADMA and SDMA and Their Impact on the L-arginine – Nitric Oxide Pathway

Cited by 5 publications

References 148 publications

Vascular nitrosative stress in hypertension induced by fetal undernutrition in rats

Vascular nitrosative stress in hypertension induced by fetal undernutrition in rats

Dysregulation of the Nitric Oxide/Dimethylarginine Pathway in Hypoxic Pulmonary Vasoconstriction—Molecular Mechanisms and Clinical Significance

Symmetric Dimethylarginine Predicts Previously Undetected Atrial Fibrillation in Patients With Ischemic Stroke

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