Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout Mice

Hannemann, Juliane; Glatzel, Antonia; Hillig, Jonas; Zummack, Julia; Schumacher, Udo; Lüneburg, Nicole; Harbaum, Lars; Böger, Rainer H.

doi:10.3389/fphys.2020.597559

Cited by 9 publications

(14 citation statements)

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“…Respiratory failure and global hypoxemia were major pathophysiological problems that led to hospital admission of the patients included in our present study. We have previously shown that ADMA continuously increases in humans exposed to chronic-intermittent hypoxia 37 , and that DDAH1 -/- mice that have high circulating ADMA concentration are prone to develop pulmonary hypertension and right ventricular hypertrophy upon exposure to chronic hypoxia 38 . Based upon our data showing that inhibitors of NO synthesis are predictive biomarkers for COVID-19 survival with high discriminative power, and in line with published pilot studies that successfully administered inhaled NO to treat severe respiratory failure 39 , 40 , therapeutic approaches aimed at restoring physiological NO function may help to better treat severe COVID-19.…”

Section: Discussionmentioning

confidence: 99%

Elevated serum SDMA and ADMA at hospital admission predict in-hospital mortality of COVID-19 patients

Hannemann

Balfanz

Schwedhelm

et al. 2021

Sci Rep

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COVID-19 is a disease with a variable clinical course ranging from mild symptoms to critical illness, organ failure, and death. Prospective biomarkers may help to predict the severity of an individual’s clinical course and mortality risk. We analyzed asymmetric (ADMA) and symmetric dimethylarginine (SDMA) in blood samples from 31 patients hospitalized for COVID-19. We calculated associations of ADMA and SDMA with mortality and organ failure, and we developed a predictive algorithm based upon these biomarkers to predict mortality risk. Nine patients (29%) experienced in-hospital death. SDMA and ADMA serum concentrations were significantly higher at admission in COVID-19 patients who died than in survivors. Cut-offs of 0.90 µmol/L for SDMA (AUC, 0.904, p = 0.0005) and 0.66 µmol/L for ADMA (AUC, 0.874, p = 0.0013) were found in ROC analyses to best discriminate both subgroups of patients. Hazard ratio for in-hospital mortality was 12.2 (95% CI: 2.2–31.2) for SDMA and 6.3 (1.1–14.7) for ADMA above cut-off. Sequential analysis of both biomarkers allowed discriminating a high-risk group (87.5% mortality) from an intermediate-risk group (25% mortality) and a low-risk group (0% mortality). Elevated circulating concentrations of SDMA and ADMA may help to better identify COVID-19 patients with a high risk of in-hospital mortality.

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Section: Discussionmentioning

confidence: 99%

Elevated serum SDMA and ADMA at hospital admission predict in-hospital mortality of COVID-19 patients

Hannemann

Balfanz

Schwedhelm

et al. 2021

Sci Rep

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“…After 6 h of hypoxia, a blood sample was collected by puncture; surviving animals were killed in anesthesia after 4 weeks of hypoxia or normoxia. Blood and tissues were collected and processed for analysis as previously described (Hannemann et al, 2020a). This study was approved by the Animal Care and Use Committee of the Freie und Hansestadt Hamburg (Approval no.…”

Section: Animals and Study Designmentioning

confidence: 99%

“…RNA preparation, reverse transcription, and quantitative realtime PCR (qRT-PCR) were performed as previously described (Hannemann et al, 2020a). Briefly, total RNA was isolated from snap-frozen, homogenized lung, liver, and renal tissues using Trizol (Thermo Fisher Scientific, Waltham, MA, United States).…”

Section: Analysis Of Agat and Gamt Mrna Expressionmentioning

confidence: 99%

“…Preparation of tissue lysates was performed as previously described (Hannemann et al, 2020a). Samples were prepared for SDS-PAGE (kidney, 30 μg total protein; liver, 50 μg total protein per lane) by boiling in beta-mercaptoethanol containing sample buffer; samples were subjected to 10% SDS-PAGE.…”

Section: Analysis Of Agat Protein Expressionmentioning

confidence: 99%

“…Increased vasoconstriction of the pulmonary vessels is assumed to play an important role, due to an increased release of vasoconstrictor prostaglandins and endothelin-1, and a reduced release of the vasodilator nitric oxide (NO; Lourenco et al, 2012;Giannakoulas et al, 2014). Accumulation of endogenous inhibitors of NO synthesis contributed to this dysregulation, and we and others have shown that chronic hypoxia induces pulmonary and cardiovascular phenotypes that are similar to PH (Hannemann et al, 2020a;Smith et al, 2020); therefore, chronic hypoxia was used as an experimental model in this study.…”

Section: Introductionmentioning

confidence: 99%

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Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia

et al. 2021

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Objective: Chronic hypoxia induces pulmonary and cardiovascular pathologies, including pulmonary hypertension (PH). L-arginine:glycine amidinotransferase (AGAT) is essential for homoarginine (hArg) and guanidinoacetate synthesis, the latter being converted to creatine by guanidinoacetate methyltransferase. Low hArg concentrations are associated with cardiovascular morbidity and predict mortality in patients with PH. We therefore aimed to investigate the survival and cardiac outcome of AGAT knockout (Agat−/−) mice under hypoxia and a possible rescue of the phenotype.Methods:Agat−/− mice and wild-type (WT) littermates were subjected to normoxia or normobaric hypoxia (10% oxygen) for 4 weeks. A subgroup of Agat−/− mice was supplemented with 1% creatine from weaning. Survival, hematocrit, blood lactate and glucose, heart weight-to-tibia length (HW/TL) ratio, hArg plasma concentration, and Agat and Gamt expression in lung, liver, and kidneys were evaluated.Results: After 6 h of hypoxia, blood lactate was lower in Agat−/−-mice as compared to normoxia (p < 0.001). Agat−/− mice died within 2 days of hypoxia, whereas Agat−/− mice supplemented with creatine and WT mice survived until the end of the study. In WT mice, hematocrit (74 ± 4 vs. 55 ± 2%, mean ± SD, p < 0.001) and HW/TL (9.9 ± 1.3 vs. 7.3 ± 0.7 mg/mm, p < 0.01) were higher in hypoxia, while hArg plasma concentration (0.25 ± 0.06 vs. 0.38 ± 0.12 μmol/L, p < 0.01) was lower. Agat and Gamt expressions were differentially downregulated by hypoxia in lung, liver, and kidneys.Conclusion:Agat and Gamt are downregulated in hypoxia. Agat−/− mice are nonviable in hypoxia. Creatine rescues the lethal phenotype, but it does not reduce right ventricular hypertrophy of Agat−/− mice in hypoxia.

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Redefining the biological and pathophysiological role of dimethylarginine dimethylaminohydrolase 2

Nair,

Mangoni,

Rodionov

2024

Trends in Molecular Medicine

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Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout Mice

Cited by 9 publications

References 31 publications

Elevated serum SDMA and ADMA at hospital admission predict in-hospital mortality of COVID-19 patients

Elevated serum SDMA and ADMA at hospital admission predict in-hospital mortality of COVID-19 patients

Arginine:Glycine Amidinotransferase Is Essential for Creatine Supply in Mice During Chronic Hypoxia

Redefining the biological and pathophysiological role of dimethylarginine dimethylaminohydrolase 2

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