Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA
Abdominal aortic aneurysm (AAA) is a common life-threatening condition characterized by exacerbated inflammation and the generation of reactive oxygen species. Pharmacological treatments to slow AAA progression or to prevent its rupture remain a challenge. Targeting phosphodiesterase 4 (PDE4) has be...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-03-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/10/3/460 |
| _version_ | 1797541249559822336 |
|---|---|
| author | Saray Varona Lídia Puertas María Galán Mar Orriols Laia Cañes Silvia Aguiló Mercedes Camacho Marc Sirvent Vicente Andrés José Martínez-González Cristina Rodríguez |
| author_facet | Saray Varona Lídia Puertas María Galán Mar Orriols Laia Cañes Silvia Aguiló Mercedes Camacho Marc Sirvent Vicente Andrés José Martínez-González Cristina Rodríguez |
| author_sort | Saray Varona |
| collection | DOAJ |
| description | Abdominal aortic aneurysm (AAA) is a common life-threatening condition characterized by exacerbated inflammation and the generation of reactive oxygen species. Pharmacological treatments to slow AAA progression or to prevent its rupture remain a challenge. Targeting phosphodiesterase 4 (PDE4) has been verified as an effective therapeutic strategy for an array of inflammatory conditions; however, no studies have assessed yet PDE4 in AAA. Here, we used angiotensin II (AngII)-infused apolipoprotein E deficient mice to study the involvement of the PDE4 subfamily in aneurysmal disease. PDE4B but not PDE4D was upregulated in inflammatory cells from both experimental and human AAA. The administration of the PDE4 selective inhibitor rolipram (3 mg/kg/day) to AngII-challenged mice (1000 ng/kg bodyweight/min) protected against AAA formation, limiting the progressive increase in the aortic diameter without affecting the blood pressure. The drug strongly attenuated the rise in vascular oxidative stress (superoxide anion) induced by AngII, and decreased the expression of inflammatory markers, as well as the recruitment of macrophages (MAC3+), lymphocytes (CD3+), and neutrophils (ELANE+) into the vessel wall. Rolipram also normalized the vascular MMP2 expression and MMP activity, preserving the elastin integrity and improving the vascular remodelling. These results point to PDE4B as a new therapeutic target for AAA. |
| first_indexed | 2024-03-10T13:12:33Z |
| format | Article |
| id | doaj.art-691a35bc3ae6496a913838e1c8713a90 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T13:12:33Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-691a35bc3ae6496a913838e1c8713a902023-11-21T10:37:49ZengMDPI AGAntioxidants2076-39212021-03-0110346010.3390/antiox10030460Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAASaray Varona0Lídia Puertas1María Galán2Mar Orriols3Laia Cañes4Silvia Aguiló5Mercedes Camacho6Marc Sirvent7Vicente Andrés8José Martínez-González9Cristina Rodríguez10Departmento de Patología Experimental, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, SpainCIBER de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, SpainCIBER de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, SpainDepartmento de Patología Experimental, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, SpainCIBER de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, SpainRegulatory Mechanisms of Cardiovascular Remodelling Group, Instituto de Investigación Biomédica Sant Pau, 08041 Barcelona, SpainCIBER de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, SpainCIBER de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, SpainCIBER de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, SpainDepartmento de Patología Experimental, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, SpainCIBER de Enfermedades Cardiovasculares, ISCIII, 28029 Madrid, SpainAbdominal aortic aneurysm (AAA) is a common life-threatening condition characterized by exacerbated inflammation and the generation of reactive oxygen species. Pharmacological treatments to slow AAA progression or to prevent its rupture remain a challenge. Targeting phosphodiesterase 4 (PDE4) has been verified as an effective therapeutic strategy for an array of inflammatory conditions; however, no studies have assessed yet PDE4 in AAA. Here, we used angiotensin II (AngII)-infused apolipoprotein E deficient mice to study the involvement of the PDE4 subfamily in aneurysmal disease. PDE4B but not PDE4D was upregulated in inflammatory cells from both experimental and human AAA. The administration of the PDE4 selective inhibitor rolipram (3 mg/kg/day) to AngII-challenged mice (1000 ng/kg bodyweight/min) protected against AAA formation, limiting the progressive increase in the aortic diameter without affecting the blood pressure. The drug strongly attenuated the rise in vascular oxidative stress (superoxide anion) induced by AngII, and decreased the expression of inflammatory markers, as well as the recruitment of macrophages (MAC3+), lymphocytes (CD3+), and neutrophils (ELANE+) into the vessel wall. Rolipram also normalized the vascular MMP2 expression and MMP activity, preserving the elastin integrity and improving the vascular remodelling. These results point to PDE4B as a new therapeutic target for AAA.https://www.mdpi.com/2076-3921/10/3/460abdominal aortic aneurysmreactive oxygen speciesPDE4Brolipram |
| spellingShingle | Saray Varona Lídia Puertas María Galán Mar Orriols Laia Cañes Silvia Aguiló Mercedes Camacho Marc Sirvent Vicente Andrés José Martínez-González Cristina Rodríguez Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA Antioxidants abdominal aortic aneurysm reactive oxygen species PDE4B rolipram |
| title | Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA |
| title_full | Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA |
| title_fullStr | Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA |
| title_full_unstemmed | Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA |
| title_short | Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA |
| title_sort | rolipram prevents the formation of abdominal aortic aneurysm aaa in mice pde4b as a target in aaa |
| topic | abdominal aortic aneurysm reactive oxygen species PDE4B rolipram |
| url | https://www.mdpi.com/2076-3921/10/3/460 |
| work_keys_str_mv | AT sarayvarona roliprampreventstheformationofabdominalaorticaneurysmaaainmicepde4basatargetinaaa AT lidiapuertas roliprampreventstheformationofabdominalaorticaneurysmaaainmicepde4basatargetinaaa AT mariagalan roliprampreventstheformationofabdominalaorticaneurysmaaainmicepde4basatargetinaaa AT marorriols roliprampreventstheformationofabdominalaorticaneurysmaaainmicepde4basatargetinaaa AT laiacanes roliprampreventstheformationofabdominalaorticaneurysmaaainmicepde4basatargetinaaa AT silviaaguilo roliprampreventstheformationofabdominalaorticaneurysmaaainmicepde4basatargetinaaa AT mercedescamacho roliprampreventstheformationofabdominalaorticaneurysmaaainmicepde4basatargetinaaa AT marcsirvent roliprampreventstheformationofabdominalaorticaneurysmaaainmicepde4basatargetinaaa AT vicenteandres roliprampreventstheformationofabdominalaorticaneurysmaaainmicepde4basatargetinaaa AT josemartinezgonzalez roliprampreventstheformationofabdominalaorticaneurysmaaainmicepde4basatargetinaaa AT cristinarodriguez roliprampreventstheformationofabdominalaorticaneurysmaaainmicepde4basatargetinaaa |