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3 FTI-277 inhibits vascular calcification by activating downstream Pi3k/Akt signalling and preventing apoptosis of vascular smooth muscle cells
  1. A Ponnusamy1,2,3,
  2. S Sinha1,3,
  3. G D Hyde1,
  4. P A Kalra3,
  5. A E Canfield1,2
  1. 1Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Manchester, UK
  2. 2NIHR Manchester Biomedical Research Center, Manchester, UK
  3. 3Salford Royal NHS Trust Foundation, Salford, UK


Vascular calcification, which involves the osteogenic differentiation of vascular smooth muscle cells (VSMC), is a major contributor to morbidity and mortality in patients with atherosclerosis, diabetes and end-stage kidney disease. We have shown that nitrogen-containing bisphosphonates attenuate vascular calcification by inhibiting farnesylpyrophosphate synthase, thereby depleting cells of farnesylpyrophosphate and geranylgeranylpyrophosphate which are essential for the prenylation and activation of small GTPases. This study aims to determine whether vascular calcification is regulated by protein prenylation. We demonstrate that a farnesyl transferase inhibitor, FTI-277, significantly inhibits β-glycerophosphate-induced calcification of VSMC in a dose-dependent manner (p<0.001). Pre-incubation of VSMCs with FTI-277 (10 μM) inhibits Ras activation and markedly enhances serum-induced Akt phosphorylation in VSMC. To determine whether FTI-277 inhibits mineralisation by promoting PI3K/Akt signalling, VSMCs were induced to mineralise in the presence of wortmannin (a PI3K inhibitor, 100 nM), FTI-277 (10 μM) or both wortmannin and FTI-277. Controls were incubated in the presence of vehicle. Wortmannin markedly promotes mineral deposition by VSMC, whereas FTI-277 inhibits mineralisation. Some mineralisation was detected in cells incubated in the presence of both reagents, demonstrating that the effects of FTI-277 can be negated, at least partially, by preventing downstream PI3K signalling. Using apoptosis assays and western blotting, we also demonstrate that FTI-277 inhibits high-phosphate-induced apoptosis of human VSMC and activation of caspase 3. These studies demonstrate that FTI-277 inhibits VSMC mineralisation, at least in part, by activating downstream PI3K/Akt signalling and preventing apoptosis. Studies are in progress to determine whether FTI-277 also regulates the osteogenic differentiation of VSMC.

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