Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA
Por:
Varona, S, Puertas, L, Galan, M, Orriols, M, Canes, L, Aguilo, S, Camacho, M, Sirvent, M, Andres, V, Martinez-Gonzalez, J, Rodriguez, C
Publicada:
1 mar 2021
Resumen:
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.
Filiaciones:
Varona, S:
Inst Invest Biomed Barcelona, Dept Patol Expt, Consejo Super Invest Cient IIBB CSIC, Barcelona 08036, Spain
CIBER Enfermedades Cardiovasc, ISCIII, Madrid 28029, Spain
Inst Invest Biomed St Pau, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08041, Spain
Puertas, L:
CIBER Enfermedades Cardiovasc, ISCIII, Madrid 28029, Spain
Inst Invest Biomed St Pau, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau IRHSCSP, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08025, Spain
Galan, M:
CIBER Enfermedades Cardiovasc, ISCIII, Madrid 28029, Spain
Inst Invest Biomed St Pau, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau IRHSCSP, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08025, Spain
Orriols, M:
Inst Invest Biomed Barcelona, Dept Patol Expt, Consejo Super Invest Cient IIBB CSIC, Barcelona 08036, Spain
CIBER Enfermedades Cardiovasc, ISCIII, Madrid 28029, Spain
Inst Invest Biomed St Pau, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08041, Spain
Canes, L:
CIBER Enfermedades Cardiovasc, ISCIII, Madrid 28029, Spain
Inst Invest Biomed St Pau, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau IRHSCSP, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08025, Spain
Aguilo, S:
Inst Invest Biomed St Pau, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau IRHSCSP, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08025, Spain
Camacho, M:
CIBER Enfermedades Cardiovasc, ISCIII, Madrid 28029, Spain
Inst Invest Biomed St Pau, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau IRHSCSP, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08025, Spain
Sirvent, M:
CIBER Enfermedades Cardiovasc, ISCIII, Madrid 28029, Spain
Hosp Badalona Germans Trias & Pujol, Angiol & Vasc Surg Serv, Badalona 08916, Spain
Andres, V:
CIBER Enfermedades Cardiovasc, ISCIII, Madrid 28029, Spain
Ctr Nacl Invest Cardiovasc Carlos III CNIC, Vasc Pathophysiol Area, Madrid 28029, Spain
Martinez-Gonzalez, J:
Inst Invest Biomed Barcelona, Dept Patol Expt, Consejo Super Invest Cient IIBB CSIC, Barcelona 08036, Spain
CIBER Enfermedades Cardiovasc, ISCIII, Madrid 28029, Spain
Inst Invest Biomed St Pau, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08041, Spain
Rodriguez, C:
CIBER Enfermedades Cardiovasc, ISCIII, Madrid 28029, Spain
Inst Invest Biomed St Pau, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08041, Spain
Inst Recerca Hosp Santa Creu & St Pau IRHSCSP, Regulatory Mech Cardiovasc Remodelling Grp, Barcelona 08025, Spain
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