PGE2 amplifies the effects of IL-1β on vascular smooth muscle cell de-differentiation: A consequence of the versatility of PGE2 receptors 3 due to the emerging expression of adenylyl cyclase 8
✍ Scribed by Nathalie Clément; Martine Glorian; Michel Raymondjean; Marise Andréani; Isabelle Limon
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- English
- Weight
- 347 KB
- Volume
- 208
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Transition of vascular smooth muscle cells from a contractile/quiescent to a secretory/proliferative phenotype is one of the critical steps in atherosclerosis and is instigated by pro‐inflammatory cytokines released from macrophages that have infiltrated into the vascular wall. In most inflammatory diseases, cell activation induced by these compounds leads to a massive production of type E~2~ prostaglandin (PGE~2~) which often takes over and even potentiates the pro‐inflammatory cytokine‐related effects. To evaluate PGE~2~ incidence on atheroma plaque development, we investigated whether and how this compound could enhance the de‐differentiation of smooth muscle cells initially induced by interleukin‐1β (IL‐1β). To address this issue, we took advantage of vascular smooth muscle cells in primary culture and tracked two markers: PLA~2~ secretion and α‐actin filament disorganization. In such a context, we found that PGE~2~ synergizes with IL‐1β to further enhance the phenotype transition of smooth muscle cells, through cAMP‐protein kinase A. As indicated by pharmacological studies, the full PGE~2~‐dependent potentiation of IL‐1β induced PLA~2~ secretion is associated with a change of regulation exerted by the subtypes 3 G~i~‐coupled PGE~2~ receptors toward adenylyl cyclase(s) activated by the subtype 4 G~s~‐linked PGE~2~ receptor. Whereas on contractile cells, stimulated subtypes 3 inhibit type 4‐dependent PLA~2~ secretion, this negative regulation is switched to positive on IL‐1β‐treated cells. Using real time PCR, pharmacological tools and small interfering RNA (siRNA), we demonstrated that the different integration of PGE~2~ signals depends on the upregulation of calcium/calmodulin stimulable adenylyl cyclase 8. J. Cell. Physiol. 208: 495–505, 2006. © 2006 Wiley‐Liss, Inc.