The effects of statin treatment on the synthesis, processing, storage and exocytosis of von Willebrand factor in cultured human endothelial cells

• Main Author: Rowlands, R J
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2011
• Subjects: Cholesterol; Lipids; Statins

The circulating, pro-thrombotic glycoprotein von Willebrand factor (VWF) is essential for haemostasis, but has also been implicated in the development of atherosclerosis. The majority of plasma VWF is secreted from endothelial cells lining the blood vessels and it is unclear what influence attenuation of the endothelial cell secretory pathway might have on the physiology or pathology of VWF. Statins are inhibitors of cholesterol biosynthesis and are widely used in the treatment of cardiovascular diseases due to their cholesterol lowering ability. However, they have also been shown this research and in the literature to have 'pleiotropic effects' caused by inhibition of the synthesis of biosynthetic intermediates (such as prenyl-lipids used for modification of small GTPases) rather than cholesterol itself. As a result this research has studied the pleiotropic actions of statins on the VWF secretory pathway in cultured human umbilical vein endothelial cells (HUVEC). As well as confirming an inhibitory effect of statins on the stimulated secretion of VWF, we found that treatment of HUVEC with statins led to a decrease in the intracellular storage of both VWF and its non-covalently associated propolypeptide (Pro-region), while the intra- and extra-cellular levels of the VWF precursor, Pro-VWF, significantly increased. All these effects were rescued by addition of the geranylgeranyl lipids used for prenylation of the Rho and Rab GTPases, but not the farnesyl lipids used for the majority of Ras family members. Using specific inhibitors of the two disitinct enzymes responsible for either Rho or Rab geranylgeranylation we have uncovered a complex picture with neither inhibitor able to reproduce all of the effects of statins of VWF. In addition to VWF, we have also discovered Rab GTPase associated effects of statins on the transferrin receptor and on the recyling of a trans Golgi network associated protein (TGN-46). In conclusion this work highlights that statins do more to vasculature than simply lowering circulating cholesterol levels and extends the complex pleiotropic effects of these drugs to influencing other cellular pathways.