Journal Article

FK506 can activate transforming growth factor-β signalling in vascular smooth muscle cells and promote proliferation

Arturo Giordano, Simona Romano, Maria Mallardo, Anna D'Angelillo, Gaetano Calì, Nicola Corcione, Paolo Ferraro and Maria Fiammetta Romano

in Cardiovascular Research

Published on behalf of European Society of Cardiology

Volume 79, issue 3, pages 519-526
Published in print August 2008 | ISSN: 0008-6363
Published online March 2008 | e-ISSN: 1755-3245 | DOI: https://dx.doi.org/10.1093/cvr/cvn079
FK506 can activate transforming growth factor-β signalling in vascular smooth muscle cells and promote proliferation

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Aims

FK506-binding protein (FKBP) 12 is an inhibitor of transforming growth factor (TGF)-β type I receptors. Several lines of evidence support the view that TGF-β stimulates vascular smooth muscle cell (VSMC) proliferation and matrix accumulation. We investigated the effect of FK506, also known as tacrolimus, on cellular proliferation and on matrix protein production in human VSMCs.

Methods and results

We measured cell proliferation with flow cytometry using BrdU incorporation and fluorimetrically by measuring DNA concentration with Hoechst 33258. Western blot assay of whole-cell lysates was used to measure the levels of signalling proteins involved in proliferative pathways, in particular β-catenin, pErk, pAkt, pmTOR, and cyclin D1. Collagen synthesis was also investigated by Western blotting. The TGF-β signal was studied by both Western blotting and confocal microscopy. We used the SiRNA technique for FKBP12 gene silencing. Our results show that FK506 stimulates VSMC proliferation and collagen type I production. FK506 enhanced β-catenin levels and activated the extracellular signal-regulated kinase, Akt, and mammalian target of rapamycin kinase, which are important effectors of proliferation. Accordingly, cyclin D1 expression was increased. We also demonstrate that FK506 activates the TGF-β signal in VSMCs and that, through this mechanism, it stimulates cell proliferation.

Conclusion

FK506 can act as a growth factor for VSMCs.

Keywords: FK506; TGF-β; VSMC; Proliferation

Journal Article.  5153 words.  Illustrated.

Subjects: Cardiovascular Medicine

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