Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension
The ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-01-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050116300092 |
| _version_ | 1830228703580258304 |
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| author | Caroline Claude Nathalie Mougenot Julia Bechaux Lahouaria Hadri Damian Brockschnieder Michel Clergue Fabrice Atassi Anne-Marie Lompré Jean-Sébastien Hulot |
| author_facet | Caroline Claude Nathalie Mougenot Julia Bechaux Lahouaria Hadri Damian Brockschnieder Michel Clergue Fabrice Atassi Anne-Marie Lompré Jean-Sébastien Hulot |
| author_sort | Caroline Claude |
| collection | DOAJ |
| description | The ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >1011 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension. |
| first_indexed | 2024-12-18T10:18:38Z |
| format | Article |
| id | doaj.art-00b59a52408a4e79b399123f71c6799f |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-18T10:18:38Z |
| publishDate | 2015-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-00b59a52408a4e79b399123f71c6799f2022-12-21T21:11:12ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012015-01-012Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertensionCaroline Claude0Nathalie Mougenot1Julia Bechaux2Lahouaria Hadri3Damian Brockschnieder4Michel Clergue5Fabrice Atassi6Anne-Marie Lompré7Jean-Sébastien Hulot8Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, ICAN, Paris, France; INSERM, UMR_S 1166, ICAN, Paris, FranceSorbonne Universités, UPMC Univ Paris 06, PECMV core, Paris, FranceSorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, ICAN, Paris, France; INSERM, UMR_S 1166, ICAN, Paris, FranceCardiovascular Research Center, Icahn School of Medicine, New York, New York, USABayer Healthcare, Global Drug Discovery, Wuppertal, GermanySorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, ICAN, Paris, France; INSERM, UMR_S 1166, ICAN, Paris, FranceSorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, ICAN, Paris, France; INSERM, UMR_S 1166, ICAN, Paris, FranceSorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, ICAN, Paris, France; INSERM, UMR_S 1166, ICAN, Paris, FranceSorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, ICAN, Paris, France; INSERM, UMR_S 1166, ICAN, Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, Department of Pharmacology & Institute of CardioMetabolism and Nutrition, Paris, FranceThe ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >1011 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension.http://www.sciencedirect.com/science/article/pii/S2329050116300092 |
| spellingShingle | Caroline Claude Nathalie Mougenot Julia Bechaux Lahouaria Hadri Damian Brockschnieder Michel Clergue Fabrice Atassi Anne-Marie Lompré Jean-Sébastien Hulot Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension Molecular Therapy: Methods & Clinical Development |
| title | Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension |
| title_full | Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension |
| title_fullStr | Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension |
| title_full_unstemmed | Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension |
| title_short | Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension |
| title_sort | inhalable delivery of aav based mrp4 abcc4 silencing rna prevents monocrotaline induced pulmonary hypertension |
| url | http://www.sciencedirect.com/science/article/pii/S2329050116300092 |
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