کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1950437 | 1537954 | 2015 | 13 صفحه PDF | دانلود رایگان |
• VSMCs transit from a contractile to a stellate morphology upon IL-1β stimulation.
• The IL-1β effect on VSMC morphology is indirect and due to the secretion of the PGE2.
• Binding to EP4, PGE2 stimulates cAMP production and PKA, modifying cell structure.
• Silencing PKAR1α -but not R1β-mimicked the effect of IL-1β/PGE2 on cell morphology.
Atherosclerosis development is associated with morphological changes to intimal cells, leading to a stellate cell phenotype. In this study, we aimed to determine whether and how key pro-atherogenic cytokines present in atherosclerotic plaques (IL-1β, TNFα and IFNγ) could induce this phenotype, as these molecules are known to trigger the transdifferentiation of vascular smooth muscle cells (VSMCs). We found that, IL-1β was the only major inflammatory mediator tested capable of inducing a stellate morphology in VSMCs. This finding was confirmed by staining for F-actin and vinculin at focal adhesions, as these two markers were disrupted only by IL-1β. We then investigated the possible association of this IL-1β-dependent change in morphology with an increase in intracellular cAMP concentration ([cAMP]), using the FRET-based biosensor for cAMP TEpacVV. Experiments in the presence of IL-1β or medium conditioned by IL-1β-treated VSMCs and pharmacological tools demonstrated that the long-term increase in intracellular cAMP concentration was induced by the secretion of an autocrine/paracrine mediator, prostaglandin E2 (PGE2), acting through the EP4 receptor. Finally, by knocking down the expression of the regulatory subunit PKAR1α, thereby reproducing the effects of IL-1β and PGE2 on VSMCs, we demonstrated the contribution of PKA activity to the observed behavior of VSMCs.
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research - Volume 1853, Issue 12, December 2015, Pages 3235–3247