Impacto del tratamiento con rolipram sobre la homeostasis rédox y la señalización celular en un modelo experimental de aneurisma de aorta abdominal

Abstract

Introduction

Cyclic nucleotide phosphodiesterases (PDEs) of the PDE4 subfamily are responsible for the hydrolysis and subcellular compartmentalization of cAMP, a second messenger that modulates vascular functionality. We had shown that PDE4B is induced in abdominal aortic aneurysms (AAA) and that PDE4 inhibition by rolipram limits experimental aneurysms. In this study we have delved into the mechanisms underlying the beneficial effect of rolipram on AAA.

Methods

AAA were induced in ApoE^-/− mice by angiotensin II (Ang II) infusion. Aneurysm formation was evaluated by ultrasonography. The expression of enzymes involved in rédox homeostasis was analyzed by real-time RT-PCR and the activation of signaling pathways by Western blot.

Results

Induction of PDE4B in human AAA has been confirmed in a second cohort of patients. In Ang II-infused ApoE^-/− mice, rolipram increased the percentage of animals free of aneurysms without affecting the percentage of aortic ruptures. Quantitative analyses determined that this drug significantly attenuated aortic collagen deposition. Additionally, rolipram reduced the increased Nox2 expression triggered by Ang II, exacerbated Sod1 induction, and normalized Sod3 expression. Likewise, PDE4 inhibition decreased the activation of both ERK1/2 and the canonical Wnt pathway, while AKT activity was not altered.

Conclusions

The inhibition of PDE4 activity modulates the expression of enzymes involved in rédox homeostasis and affects cell signaling pathways involved in the development of AAA.