期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
卷 1853, 期 12, 页码 3235-3247出版社
ELSEVIER
DOI: 10.1016/j.bbamcr.2015.09.019
关键词
Vascular smooth muscle cells; IL-1 beta; PGE(2); cAMP; PKA; stellate cell morphology
资金
- Paris VI University
- national research agency [11 BSV1 034 01]
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-1 beta, TNF alpha and IFN gamma) could induce this phenotype, as these molecules are known to trigger the transdifferentiation of vascular smooth muscle cells (VSMCs). We found that, IL-1 beta 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-1 beta. We then investigated the possible association of this IL-1 beta-dependent change in morphology with an increase in intracellular CAMP concentration ([cAMP]), using the FRET-based biosensor for CAMP (T)Epac(VV). Experiments in the presence of IL-1 beta or medium conditioned by IL-1 beta-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 E-2 (PGE(2)), acting through the EP4 receptor. Finally, by knocking down the expression of the regulatory subunit PKAR1 alpha, thereby reproducing the effects of IL-1 beta and PGE(2) on VSMCs, we demonstrated the contribution of PICA activity to the observed behavior of VSMCs. (C) 2015 Elsevier B.V. All rights reserved.
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