The Role of Prenylation in Vascular Calcification

Abstract

Vascular calcification is an active, regulated process in which vascular smooth muscle cells (VSMCs) differentiate into osteoblast-like cells and deposit a mineralised matrix. It is well established that patients with chronic kidney disease and diabetes have poor cardiovascular outcomes which is thought to be due to increased vascular calcification and atherosclerosis. Previous work from the host laboratory has shown that nitrogen-containing bisphosphonates attenuate vascular calcification by inhibiting farnesyl pyrophosphate synthase, depleting cells of farnesyl pyrophosphate and geranylgeranyl pyrophosphate which are essential for the prenylation and activation of small GTPases such as Ras and Rho. Therefore, the initial aim of this study was to determine the effects of farnesyl transferase inhibitors (FTI-277 and manumycin A) on vascular calcification using a well validated in vitro model in which VSMCs are induced to deposit a mineralised matrix in the presence of β-glycerophosphate. FTI-277 significantly inhibited β-glycerophosphate-induced calcification of VSMCs in vitro (p

Date of Award	1 Aug 2014
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Ann Canfield (Supervisor) & Philip Kalra (Supervisor)