Impacts of intracellular lipid mobilisation on endothelial dysfunction

Abstract

Lipid metabolism and transport are important for the development of cardiovascular diseases (CVD). Oxysterol-binding related proteins-2 (ORP2) is the only known lipid transporter to transport cholesterol on the plasma membrane (PM). Knockdown of ORP2 in human umbilical vein endothelial cells (HUVEC) shows downregulation of pro-inflammatory signals under endothelial activation induced by TNF- and turbulent flow. Knockdown of ORP2 can also disrupt the endothelial recruitment of monocytes. However, deficiency of ORP2 does not alter the expression of lipid rafts structural proteins Flotllin-1 and Caveolae-1.

Additionally, expression of ORP2 is found to be upregulated in endothelial senescence. Knockdown of ORP2 after oxidative stress stimulation can efficiently block the progress of senescence. On the other hand, lipid profiling of hydrogen peroxide (H2O2) induced endothelial senescence was conducted with a combination of targeted and untargeted lipidomics analysis. A total of 336 lipid species have been analysed so far in this study. Alterations of lipids during the progression of senescence were found in classes of sphingolipid, glycerophospholipid, free fatty acid and cholesterol.

Overall, this thesis provides evidence of the importance of ORP2 in CVD and the endothelial senescent lipidome profile. These results give insights for research on cardiovascular disease and cellular senescence mechanisms. Future work will expand lipid profiling to include more lipid species in this study and testify to the function of ORP2 in animal models and subcellular structure.