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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.

FTI-277 inhibits smooth muscle cell calcification by up-regulating PI3K/Akt signaling and inhibiting apoptosis Thumbnail


Authors

Arvind Ponnusamy

Smeeta Sinha

Gareth D. Hyde

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

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