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Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA
Saray Varona1,2,3, Lídia Puertas2,3,4, María Galán2,3,4
1Departmento de Patología Experimental, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas (IIBB-CSIC), 08036 Barcelona, Spain.
Abstract:
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.
Insights
Targeting phosphodiesterase 4B (PDE4B) may offer a new treatment for abdominal aortic aneurysm (AAA). Inhibiting PDE4B with rolipram reduced AAA progression in mice by decreasing inflammation and oxidative stress.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Inflammation Biology
Background:
- Abdominal aortic aneurysm (AAA) is a dangerous condition driven by inflammation and oxidative stress, with limited treatment options.
- Phosphodiesterase 4 (PDE4) is a potential therapeutic target for inflammatory diseases, but its role in AAA is unexplored.
Purpose of the Study:
- To investigate the role of the PDE4 enzyme subfamily in the development of abdominal aortic aneurysm.
- To evaluate the therapeutic potential of PDE4 inhibition in a mouse model of AAA.
Main Methods:
- Angiotensin II (AngII)-infused apolipoprotein E deficient mice were used to model AAA.
- The PDE4 selective inhibitor rolipram was administered to assess its effects on AAA formation and progression.
- Vascular oxidative stress, inflammatory cell infiltration, matrix metalloproteinase (MMP) activity, and elastin integrity were analyzed.
Main Results:
- PDE4B, but not PDE4D, was upregulated in inflammatory cells in both experimental and human AAA.
- Rolipram treatment significantly protected against AAA formation and limited aortic diameter increase without affecting blood pressure.
- Rolipram attenuated vascular oxidative stress, reduced inflammatory cell infiltration (macrophages, lymphocytes, neutrophils), normalized MMP2 expression and activity, and preserved elastin integrity.
Conclusions:
- PDE4B is upregulated in AAA and plays a significant role in its pathogenesis.
- Selective PDE4B inhibition represents a promising therapeutic strategy for preventing AAA progression and rupture.
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