Biopterin metabolism and eNOS expression during hypoxic pulmonary hypertension in mice.
Tetrahydrobiopterin (BH4), which fosters the formation of and stabilizes endothelial NO synthase (eNOS) as an active dimer, tightly regulates eNOS coupling / uncoupling. Moreover, studies conducted in genetically-modified models demonstrate that BH4 pulmonary deficiency is a key determinant in the p...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3842263?pdf=render |
| _version_ | 1818369191126761472 |
|---|---|
| author | Mathilde Dubois Estelle Delannoy Lucie Duluc Ellen Closs Huige Li Christian Toussaint Alain-Pierre Gadeau Axel Gödecke Véronique Freund-Michel Arnaud Courtois Roger Marthan Jean-Pierre Savineau Bernard Muller |
| author_facet | Mathilde Dubois Estelle Delannoy Lucie Duluc Ellen Closs Huige Li Christian Toussaint Alain-Pierre Gadeau Axel Gödecke Véronique Freund-Michel Arnaud Courtois Roger Marthan Jean-Pierre Savineau Bernard Muller |
| author_sort | Mathilde Dubois |
| collection | DOAJ |
| description | Tetrahydrobiopterin (BH4), which fosters the formation of and stabilizes endothelial NO synthase (eNOS) as an active dimer, tightly regulates eNOS coupling / uncoupling. Moreover, studies conducted in genetically-modified models demonstrate that BH4 pulmonary deficiency is a key determinant in the pathogenesis of pulmonary hypertension. The present study thus investigates biopterin metabolism and eNOS expression, as well as the effect of sepiapterin (a precursor of BH4) and eNOS gene deletion, in a mice model of hypoxic pulmonary hypertension. In lungs, chronic hypoxia increased BH4 levels and eNOS expression, without modifying dihydrobiopterin (BH2, the oxidation product of BH4) levels, GTP cyclohydrolase-1 or dihydrofolate reductase expression (two key enzymes regulating BH4 availability). In intrapulmonary arteries, chronic hypoxia also increased expression of eNOS, but did not induce destabilisation of eNOS dimers into monomers. In hypoxic mice, sepiapterin prevented increase in right ventricular systolic pressure and right ventricular hypertrophy, whereas it modified neither remodelling nor alteration in vasomotor responses (hyper-responsiveness to phenylephrine, decrease in endothelium-dependent relaxation to acetylcholine) in intrapulmonary arteries. Finally, deletion of eNOS gene partially prevented hypoxia-induced increase in right ventricular systolic pressure, right ventricular hypertrophy and remodelling of intrapulmonary arteries. Collectively, these data demonstrate the absence of BH4/BH2 changes and eNOS dimer destabilisation, which may induce eNOS uncoupling during hypoxia-induced pulmonary hypertension. Thus, even though eNOS gene deletion and sepiapterin treatment exert protective effects on hypoxia-induced pulmonary vascular remodelling, increase on right ventricular pressure and / or right ventricular hypertrophy, these effects appear unrelated to biopterin-dependent eNOS uncoupling within pulmonary vasculature of hypoxic wild-type mice. |
| first_indexed | 2024-12-13T23:19:55Z |
| format | Article |
| id | doaj.art-daf2ff7938b441cca853d75689a580ad |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T23:19:55Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-daf2ff7938b441cca853d75689a580ad2022-12-21T23:27:48ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01811e8259410.1371/journal.pone.0082594Biopterin metabolism and eNOS expression during hypoxic pulmonary hypertension in mice.Mathilde DuboisEstelle DelannoyLucie DulucEllen ClossHuige LiChristian ToussaintAlain-Pierre GadeauAxel GödeckeVéronique Freund-MichelArnaud CourtoisRoger MarthanJean-Pierre SavineauBernard MullerTetrahydrobiopterin (BH4), which fosters the formation of and stabilizes endothelial NO synthase (eNOS) as an active dimer, tightly regulates eNOS coupling / uncoupling. Moreover, studies conducted in genetically-modified models demonstrate that BH4 pulmonary deficiency is a key determinant in the pathogenesis of pulmonary hypertension. The present study thus investigates biopterin metabolism and eNOS expression, as well as the effect of sepiapterin (a precursor of BH4) and eNOS gene deletion, in a mice model of hypoxic pulmonary hypertension. In lungs, chronic hypoxia increased BH4 levels and eNOS expression, without modifying dihydrobiopterin (BH2, the oxidation product of BH4) levels, GTP cyclohydrolase-1 or dihydrofolate reductase expression (two key enzymes regulating BH4 availability). In intrapulmonary arteries, chronic hypoxia also increased expression of eNOS, but did not induce destabilisation of eNOS dimers into monomers. In hypoxic mice, sepiapterin prevented increase in right ventricular systolic pressure and right ventricular hypertrophy, whereas it modified neither remodelling nor alteration in vasomotor responses (hyper-responsiveness to phenylephrine, decrease in endothelium-dependent relaxation to acetylcholine) in intrapulmonary arteries. Finally, deletion of eNOS gene partially prevented hypoxia-induced increase in right ventricular systolic pressure, right ventricular hypertrophy and remodelling of intrapulmonary arteries. Collectively, these data demonstrate the absence of BH4/BH2 changes and eNOS dimer destabilisation, which may induce eNOS uncoupling during hypoxia-induced pulmonary hypertension. Thus, even though eNOS gene deletion and sepiapterin treatment exert protective effects on hypoxia-induced pulmonary vascular remodelling, increase on right ventricular pressure and / or right ventricular hypertrophy, these effects appear unrelated to biopterin-dependent eNOS uncoupling within pulmonary vasculature of hypoxic wild-type mice.http://europepmc.org/articles/PMC3842263?pdf=render |
| spellingShingle | Mathilde Dubois Estelle Delannoy Lucie Duluc Ellen Closs Huige Li Christian Toussaint Alain-Pierre Gadeau Axel Gödecke Véronique Freund-Michel Arnaud Courtois Roger Marthan Jean-Pierre Savineau Bernard Muller Biopterin metabolism and eNOS expression during hypoxic pulmonary hypertension in mice. PLoS ONE |
| title | Biopterin metabolism and eNOS expression during hypoxic pulmonary hypertension in mice. |
| title_full | Biopterin metabolism and eNOS expression during hypoxic pulmonary hypertension in mice. |
| title_fullStr | Biopterin metabolism and eNOS expression during hypoxic pulmonary hypertension in mice. |
| title_full_unstemmed | Biopterin metabolism and eNOS expression during hypoxic pulmonary hypertension in mice. |
| title_short | Biopterin metabolism and eNOS expression during hypoxic pulmonary hypertension in mice. |
| title_sort | biopterin metabolism and enos expression during hypoxic pulmonary hypertension in mice |
| url | http://europepmc.org/articles/PMC3842263?pdf=render |
| work_keys_str_mv | AT mathildedubois biopterinmetabolismandenosexpressionduringhypoxicpulmonaryhypertensioninmice AT estelledelannoy biopterinmetabolismandenosexpressionduringhypoxicpulmonaryhypertensioninmice AT lucieduluc biopterinmetabolismandenosexpressionduringhypoxicpulmonaryhypertensioninmice AT ellencloss biopterinmetabolismandenosexpressionduringhypoxicpulmonaryhypertensioninmice AT huigeli biopterinmetabolismandenosexpressionduringhypoxicpulmonaryhypertensioninmice AT christiantoussaint biopterinmetabolismandenosexpressionduringhypoxicpulmonaryhypertensioninmice AT alainpierregadeau biopterinmetabolismandenosexpressionduringhypoxicpulmonaryhypertensioninmice AT axelgodecke biopterinmetabolismandenosexpressionduringhypoxicpulmonaryhypertensioninmice AT veroniquefreundmichel biopterinmetabolismandenosexpressionduringhypoxicpulmonaryhypertensioninmice AT arnaudcourtois biopterinmetabolismandenosexpressionduringhypoxicpulmonaryhypertensioninmice AT rogermarthan biopterinmetabolismandenosexpressionduringhypoxicpulmonaryhypertensioninmice AT jeanpierresavineau biopterinmetabolismandenosexpressionduringhypoxicpulmonaryhypertensioninmice AT bernardmuller biopterinmetabolismandenosexpressionduringhypoxicpulmonaryhypertensioninmice |