Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout Mice
Objective: Chronic hypoxia causes pulmonary vasoconstriction leading to pulmonary hypertension and right ventricular hypertrophy. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis; its level increases in hypoxia (HX) concomitantly with reduced activity of d...
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| Format: | Article |
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Frontiers Media S.A.
2020-11-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2020.597559/full |
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| author | Juliane Hannemann Juliane Hannemann Antonia Glatzel Jonas Hillig Jonas Hillig Julia Zummack Julia Zummack Udo Schumacher Nicole Lüneburg Lars Harbaum Rainer Böger Rainer Böger |
| author_facet | Juliane Hannemann Juliane Hannemann Antonia Glatzel Jonas Hillig Jonas Hillig Julia Zummack Julia Zummack Udo Schumacher Nicole Lüneburg Lars Harbaum Rainer Böger Rainer Böger |
| author_sort | Juliane Hannemann |
| collection | DOAJ |
| description | Objective: Chronic hypoxia causes pulmonary vasoconstriction leading to pulmonary hypertension and right ventricular hypertrophy. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis; its level increases in hypoxia (HX) concomitantly with reduced activity of dimethylarginine dimethylaminohydrolases (DDAH-1 and DDAH-2), enzymes metabolizing ADMA. Ddah1 knockout (KO) mice may therefore help to understand the pathophysiological roles of this enzyme and its substrate, ADMA, in the development of hypoxia-associated pulmonary hypertension.Methods: Ddah1 KO mice and their wild-type (WT) littermates were subjected to normoxia (NX) or for 21 days. We measured ADMA concentration in plasma and lungs, DDAH1 and DDAH2 mRNA and protein expression in the lungs, right ventricular systolic pressure (RVSP), right ventricular hypertrophy by the Fulton index, and cardiomyocyte hypertrophy by dystrophin staining of the heart.Results: Ddah1 KO mice had higher ADMA concentrations in plasma and in lung tissue than WT in NX (p < 0.05). ADMA significantly increased in WT-HX in plasma and lungs, while there were no significant differences in WT-HX vs. KO-HX. This finding was paralleled by a 38 ± 13% reduction in Ddah1 but not Ddah2 mRNA expression, and reduced DDAH1 protein expression but stable DDAH2 protein levels in WT mice. Ddah1 KO mice showed significant elevation of DDAH2 protein but not mRNA levels, which further increased in HX. HX led to increased RVSP and right ventricular hypertrophy in both, WT and KO mice, with no significant differences between both genotypes.Conclusions: Chronic hypoxia causes an elevation of ADMA, which may impair NO production and lead to endothelial dysfunction and vasoconstriction. Downregulation of DDAH1 expression and activity may be involved in this; however, knockout of the Ddah1 gene does not modify the hypoxia-induced pathophysiological changes of pulmonary blood pressure and right ventricular hypertrophy, possibly due to compensatory upregulation of DDAH2 protein. |
| first_indexed | 2024-12-13T05:37:39Z |
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| id | doaj.art-23f414721f934f21b8ba3e34634f5862 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-13T05:37:39Z |
| publishDate | 2020-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Physiology |
| spelling | doaj.art-23f414721f934f21b8ba3e34634f58622022-12-21T23:57:52ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2020-11-011110.3389/fphys.2020.597559597559Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout MiceJuliane Hannemann0Juliane Hannemann1Antonia Glatzel2Jonas Hillig3Jonas Hillig4Julia Zummack5Julia Zummack6Udo Schumacher7Nicole Lüneburg8Lars Harbaum9Rainer Böger10Rainer Böger11Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute DECIPHER (German-Chilean Institute for Research on Pulmonary Hypoxia and Its Health Sequelae), Hamburg, GermanyInstitute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute DECIPHER (German-Chilean Institute for Research on Pulmonary Hypoxia and Its Health Sequelae), Hamburg, GermanyInstitute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute DECIPHER (German-Chilean Institute for Research on Pulmonary Hypoxia and Its Health Sequelae), Hamburg, GermanyInstitute of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Pulmonology, II. Medical Clinic and Policlinic, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute DECIPHER (German-Chilean Institute for Research on Pulmonary Hypoxia and Its Health Sequelae), Hamburg, GermanyObjective: Chronic hypoxia causes pulmonary vasoconstriction leading to pulmonary hypertension and right ventricular hypertrophy. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis; its level increases in hypoxia (HX) concomitantly with reduced activity of dimethylarginine dimethylaminohydrolases (DDAH-1 and DDAH-2), enzymes metabolizing ADMA. Ddah1 knockout (KO) mice may therefore help to understand the pathophysiological roles of this enzyme and its substrate, ADMA, in the development of hypoxia-associated pulmonary hypertension.Methods: Ddah1 KO mice and their wild-type (WT) littermates were subjected to normoxia (NX) or for 21 days. We measured ADMA concentration in plasma and lungs, DDAH1 and DDAH2 mRNA and protein expression in the lungs, right ventricular systolic pressure (RVSP), right ventricular hypertrophy by the Fulton index, and cardiomyocyte hypertrophy by dystrophin staining of the heart.Results: Ddah1 KO mice had higher ADMA concentrations in plasma and in lung tissue than WT in NX (p < 0.05). ADMA significantly increased in WT-HX in plasma and lungs, while there were no significant differences in WT-HX vs. KO-HX. This finding was paralleled by a 38 ± 13% reduction in Ddah1 but not Ddah2 mRNA expression, and reduced DDAH1 protein expression but stable DDAH2 protein levels in WT mice. Ddah1 KO mice showed significant elevation of DDAH2 protein but not mRNA levels, which further increased in HX. HX led to increased RVSP and right ventricular hypertrophy in both, WT and KO mice, with no significant differences between both genotypes.Conclusions: Chronic hypoxia causes an elevation of ADMA, which may impair NO production and lead to endothelial dysfunction and vasoconstriction. Downregulation of DDAH1 expression and activity may be involved in this; however, knockout of the Ddah1 gene does not modify the hypoxia-induced pathophysiological changes of pulmonary blood pressure and right ventricular hypertrophy, possibly due to compensatory upregulation of DDAH2 protein.https://www.frontiersin.org/articles/10.3389/fphys.2020.597559/fullhypoxianitric oxidehypoxic vasoconstrictionendotheliumADMADDAH |
| spellingShingle | Juliane Hannemann Juliane Hannemann Antonia Glatzel Jonas Hillig Jonas Hillig Julia Zummack Julia Zummack Udo Schumacher Nicole Lüneburg Lars Harbaum Rainer Böger Rainer Böger Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout Mice Frontiers in Physiology hypoxia nitric oxide hypoxic vasoconstriction endothelium ADMA DDAH |
| title | Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout Mice |
| title_full | Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout Mice |
| title_fullStr | Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout Mice |
| title_full_unstemmed | Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout Mice |
| title_short | Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout Mice |
| title_sort | upregulation of ddah2 limits pulmonary hypertension and right ventricular hypertrophy during chronic hypoxia in ddah1 knockout mice |
| topic | hypoxia nitric oxide hypoxic vasoconstriction endothelium ADMA DDAH |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2020.597559/full |
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