dimethylarginine and Hypoxia

Lüneburg, Nicole, Patricia Siques, Julio Brito, Juan José De La Cruz, Fabiola León-Velarde, Juliane Hannemann, Cristian Ibanez, and Rainer Böger. Long-term intermittent exposure to high altitude elevates asymmetric dimethylarginine in first exposed young adults. High Alt Med Biol. 18:226-233, 2017.-Hypoxia-induced dysregulation of pulmonary and cerebral circulation may be related to an impaired nitric oxide (NO) pathway. We investigated the effect of chronic intermittent hypobaric hypoxia (CIH) on metabolites of the NO pathway. We measured asymmetric and symmetric dimethylarginine (ADMA and SDMA) and monomethyl-L-arginine (L-NMMA) and assessed their associations with acclimatization in male draftees (n = 72) undergoing CIH shifts at altitude (3550 m) during 3 months. Sixteen Andean natives living at altitude (3675 m) (chronic hypobaric hypoxia [CH]) were included for comparison. In CIH, ADMA and L-NMMA plasma concentrations increased from 1.14 ± 0.04 to 1.95 ± 0.09 μmol/L (mean ± SE) and from 0.22 ± 0.07 to 0.39 ± 0.03 μmol/L, respectively, (p < 0.001 for both) after 3 months, whereas SDMA did not change. The concentrations of ADMA and L-NMMA were higher in CH (3.48 ± 0.07, 0.53 ± 0.08 μmol/L; p < 0.001) as compared with CIH. In both CIH and CH, ADMA correlated with hematocrit (r

Topics: Acclimatization; Adolescent; Altitude; Altitude Sickness; Arginine; Chile; Humans; Hypoxia; Male; Military Personnel; Occupational Diseases; omega-N-Methylarginine; Young Adult

To define the clinical significance of asymmetric dimethylarginine (ADMA) and that of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism as factors of endothelial dysfunction (ED) in the development of early kidney injury in obese patients.. The investigation included 86 patients (64 men and 22 women aged 44 +/- 11 years) with abdominal obesity. Along with physical examination, the authors determined albuminuria, calculated glomerular filtration rate (GFR) using the Modification of Diet in Renal Disease (MDRD) formula, estimated insulin resistance markers (fasting plasma insulin and C-peptide concentrations and homeostatic model assessment (HOMA) index), as well as serum ADMA levels by enzyme immunoassay in all the patients. C677T polymorphism in the MTHFR gene was studied by allele-specific polymerase chain reaction and restriction fragment length polymorphism analysis. Kidney injury (chronic kidney disease (CKD)) was diagnosed using the Kidney Disease Outcomes Quality Initiative (KDOQI) criteria. Early vascular remodeling was determined from the increased intima-media thickness (IMT) of the common carotid artery (CCA).. CKD was diagnosed in 27(31%) patients. The latter, unlike the patients with CKD, were observed to have more pronounced obesity (body mass index (BMI) 36.8 +/- 8.0 and 32.0 +/- 4.7 kg/m2, respectively (p < 0.001)), waist circumference (119 +/- 18 and 109 +/- 11 cm (p = 0.002)), higher levels of C-peptide (1348 +/- 363 and 1028 +/- 363 pmol/I; p < 0.001), insulin (16.9 +/- 7.3 and 11.7 +/- 5.5 microU/ ml; p < 0.001), and HOMA index (4.3 +/- 1.7 and 2.9 +/- 1.5; p < 0.001). In the patients with Stage IIIa CKD, ADMA concentrations (0.77 +/- 0.19 micromol/l) was higher than in those with Stages I (0.58 +/- 0.11 micromol/l; p = 0.048) and II (0.61 +/- 0.13 micromol/l; p = 0.071). An association between ADMA concentrations, CCA IMT, and estimated GFR was revealed in the patients with CKD. The predictors of an estimated GFR reduction in obesity were elevated serum concentrations of ADMA, uric acid, insulin, and HOMA index. The combination of obstructive sleep apnea syndrome and metabolic syndrome increased the risk of CKD by 2.1-fold (95% confidence interval, 1.06-3.14). Evaluation of the impact of MTHFR gene polymorphism on kidney injury in obesity disclosed that the patients with homozygous carriage of the abnormal T allele of the MTHFR gene had a higher risk for Stages I-IIIa CKD (2.60 with 95% confidence interval, 1.32-3.88), more marked obesity and hyperinsulinemia, and increased serum ADMA concentrations.. Insulin resistance and ED hold a central position in the pathogenesis of CKD in obese patients. The mechanisms of the atherosclerotic vascular remodeling associated with elevated serum ADMA concentrations are of paramount importance in the progression of early-stage CKD. The homozygous carriage of the abnormal T allele of the MTHFR gene increases the risk of Stages I-IIIa by more than twice.

Topics: Adult; Arginine; Carotid Artery, Common; Data Interpretation, Statistical; Endothelium, Vascular; Female; Glomerular Filtration Rate; Humans; Hypoxia; Insulin Resistance; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Obesity; Polymorphism, Genetic; Renal Insufficiency, Chronic; Risk Factors; Severity of Illness Index; Tunica Media; Ultrasonography

To identify a possible role for nitric oxide (NO) in acute hypoxic tolerance (HT) we measured hypoxic survival time (HST), effect of hypoxic conditioning (HC), and survival following hypoxic conditioning while blocking or mimicking the action of nitric oxide synthase (NOS). To inhibit NOS, CD-1 mice were given supplemental endogenous NOS inhibitor asymmetrical dimethylarginine (ADMA) or a synthetic NOS inhibitor N(omega)-nitro-L-arginine (L-NNA), both of which nonselectively inhibit three of the isoforms of NOS [inducible (iNOS), neuronal (nNOS), and endothelial NOS (eNOS)]. ADMA (10 mg/kg i.p.) or saline vehicle was given 5 min before HST testing. L-NNA was given orally at 1 g/l in drinking water with tap water as the control for 48 h before testing. Both ADMA and L-NNA significantly increased HST and augmented the HC effect on HST. Neither the nNOS selective inhibitor 7-nitroindazole (7-NI) nor the iNOS selective inhibitor N-{[3-(aminomethyl)phenyl]methyl}-enthanimidamide (1400W) had a statistically significant effect on HST or HT. The NO donor, 3-morpholinosydnoeimine, when given alone did not significantly decrease HT, but it did mitigate the increased HT effect of L-NNA. These data confirm that acute hypoxic conditioning increases HT and that NOS inhibition by endogenous (ADMA) and a synthetic NOS inhibitor (L-NNA) further increases HT, whereas iNOS and nNOS inhibition does not, suggesting that it is the inhibition of eNOS that mediates enhancement of HT.

Topics: Acute Disease; Animals; Arginine; Endothelium, Vascular; Enzyme Inhibitors; Hypoxia; Imines; Indazoles; Male; Mice; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroarginine; Time Factors

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthesis. ADMA is generated by catabolism of proteins containing methylated arginine residues, and its levels are correlated with endothelial dysfunction in systemic cardiovascular diseases. Arginine methylation of cellular proteins is catalyzed by protein arginine methyltransferases (PRMT). The expression and localization of PRMT in the lung has not been addressed. Here, we sought to analyze the expression of PRMT isoforms in the lung and to determine whether PRMT expression is altered during exposure to chronic hypoxia (10% oxygen). Adult mice were exposed to hypoxia for up to 3 wk, and lung tissues were harvested and processed for RT-PCR, Western blotting, immunohistochemistry, and determination of tissue ADMA levels. All PRMT isoforms investigated were detected at the mRNA and protein level in mouse lung, and were localized primarily to the bronchial and alveolar epithelium. In lungs of mice subjected to chronic hypoxia, PRMT2 mRNA and protein levels were up-regulated, whereas the expression of all other PRMT isoforms remained unchanged. This was mainly due to increased expression of PRMT2 in alveolar type II cells, which did not express detectable levels of PRMT2 under normoxic conditions. Consistent with these observations, lung ADMA levels and ADMA/l-Arginine ratios were increased under hypoxic conditions. These results demonstrate that PRMTs are expressed and functional in the lung, and that hypoxia is a potent regulator of PRMT2 expression and lung ADMA concentrations. These data suggest that structural and functional changes caused by hypoxia may be linked to ADMA metabolism.

Topics: Animals; Arginine; Hypoxia; Isoenzymes; Lung; Male; Methylation; Mice; Mice, Inbred BALB C; Protein-Arginine N-Methyltransferases