Arvind Ponnusamy
FTI-277 inhibits smooth muscle cell calcification by up-regulating PI3K/Akt signaling and inhibiting apoptosis
Ponnusamy, Arvind; Sinha, Smeeta; Hyde, Gareth D.; Borland, Samantha J.; Taylor, Rebecca F.; Pond, Emma; Eyre, Heather J.; Inkson, Colette A.; Gilmore, Andrew; Ashton, Nick; Kalra, Philip A.; Canfield, Ann E.
Authors
Smeeta Sinha
Gareth D. Hyde
Dr Samantha Borland S.Borland@salford.ac.uk
Lecturer
Rebecca F. Taylor
Emma Pond
Heather J. Eyre
Colette A. Inkson
Andrew Gilmore
Nick Ashton
Philip A. Kalra
Ann E. Canfield
Contributors
Yin Tintut
Editor
Abstract
Background
Vascular calcification is associated with increased cardiovascular morbidity and mortality in patients with atherosclerosis, diabetes and chronic kidney disease. However, no viable treatments for this condition have been identified. This study aimed to determine whether farnesyl transferase inhibitors (FTIs) can reduce vascular calcification and the mechanism by which this reduction occurs.
Results
We demonstrate that FTI-277 significantly inhibits phosphate-induced mineral deposition by vascular smooth muscle cells (VSMC) in vitro, prevents VSMC osteogenic differentiation, and increases mRNA expression of matrix Gla protein (MGP), an inhibitor of mineralization. FTI-277 increases Akt signaling in VSMC in short-term serum-stimulation assays and in long-term mineralization assays. In contrast, manumycin A has no effect on Akt signaling or mineralization. Co-incubation of VSMC with FTI-277 and SH6 (an Akt inhibitor) significantly reduces the inhibitory effect of FTI-277 on mineralization, demonstrating that FTI-277 inhibits calcification by activating Akt signaling. Over-expression of the constitutively active p110 sub-unit of PI3K in VSMC using adenovirus activates Akt, inhibits mineralization, suppresses VSMC differentiation and significantly enhances MGP mRNA expression. FTI-277 also inhibits phosphate-induced activation of caspase 3 and apoptosis of VSMC, and these effects are negated by co-incubation with SH6. Finally, using an ex vivo model of vascular calcification, we demonstrate that FTI-277 inhibits high phosphate-induced mineralization in aortic rings derived from rats with end-stage renal failure.
Conclusions
Together, these results demonstrate that FTI-277 inhibits VSMC mineral deposition by up-regulating PI3K/Akt signaling and preventing apoptosis, suggesting that targeting farnesylation, or Akt specifically, may have therapeutic potential for the prevention of vascular calcification.
Journal Article Type | Article |
---|---|
Acceptance Date | Apr 9, 2018 |
Online Publication Date | Apr 24, 2018 |
Publication Date | Apr 24, 2018 |
Deposit Date | Aug 20, 2024 |
Publicly Available Date | Sep 19, 2024 |
Journal | PLOS ONE |
Print ISSN | 1932-6203 |
Publisher | Public Library of Science |
Peer Reviewed | Peer Reviewed |
Volume | 13 |
Issue | 4 |
Article Number | e0196232 |
DOI | https://doi.org/10.1371/journal.pone.0196232 |
Files
Published Version
(12.4 Mb)
PDF
Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
You might also like
Self-assembling peptide hydrogel for intervertebral disc tissue engineering
(2016)
Journal Article
Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease
(2020)
Preprint / Working Paper
Downloadable Citations
About USIR
Administrator e-mail: library-research@salford.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2025
Advanced Search