The involvement of modified lipids in vascular injury and disease

Greig, Fiona Helen (2013) The involvement of modified lipids in vascular injury and disease. PhD thesis, University of Glasgow.

Abstract

Atherosclerosis is characterised by the deposition and accumulation of modified lipids in the subendothelial space of the arterial wall, as well as vascular remodelling leading to atherosclerotic plaque formation. Restenosis is a known complication of the surgical interventions used to treat atherosclerosis and results in neointimal thickening, in part by the action of vascular smooth muscle cells (VSMCs). Various physiological effects have previously been attributed to the action of oxidised low density lipoproteins leading to an exacerbation of the inflammatory response and vascular remodelling processes in atherosclerosis and restenosis. Little is known to date about the effects of individual modified lipids generated by the action of phagocytic myeloperoxidase (MPO) on these processes. The aim of the present study was to investigate the biological effects of modified lipids, both chlorinated and oxidised species, in vascular injury and disease, focussing primarily on their effects on vascular smooth muscle (VSM). Primary VSMCs were used to examine the effects of these modified lipids at a cellular level. Chlorinated lipids, phospholipid chlorohydrins and alpha-chloro fatty aldehydes were found to have a limited effect on VSMC proliferation, viability or migration whereas, oxidised phospholipids caused a concentration-dependent reduction in all of these vascular remodelling processes. As AMP-activated protein kinase (AMPK) has recently been implicated in vascular disease and found to exert anti-apoptotic effects, the impact of AMPK signalling on the effects of the modified lipids in VSM was assessed. Activation of AMPK prior to incubation of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine chlorohydrin resulted in an increase in VSMC proliferation while a greater level of VSMC death was observed after treatment with the oxidised phospholipid, 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine than with the lipids alone. The occurrence of these modified lipids in neointima formation was subsequently investigated using a carotid artery injury model in healthy and atherosclerotic mice (mice deficient in apolipoprotein E, ApoE-/-). Neointimal growth and levels of plasma MPO were increased in ApoE-/- mice resulting in elevated levels of lysophosphatidylcholines and altered relative proportions of phosphatidylcholines (PCs) in injured carotid arteries compared to their contralateral uninjured right carotid arteries. Finally, in vivo AMPK activation by administration of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) in healthy and atherosclerotic mice and its effect on the lipid profile of the aorta were characterised. Chronic AMPK activation resulted in a reduction in mean arterial and diastolic pressures as well as a dramatic increase in pulse pressure in ApoE-/- mice compared to their saline-treated littermates. Plasma MPO was elevated in AICAR-treated ApoE-/- mice with an alteration in the relative intensities of PCs in aortae of AMPK activated ApoE-/- mice. The present study is the first report of divergent effects of different classes of modified lipids on vascular remodelling processes and how these processes may be modulated by AMPK signalling in VSM in atherosclerosis. In addition, this study has generated novel data on the relative changes in distribution of PCs in carotid arteries after vascular injury as well as in aortic tissue of healthy and atherosclerotic mice after AMPK activation. Additional analysis is required to confirm these differences which could offer further insight into the involvement of modified lipids in vascular diseases. This study has also highlighted a novel interaction of AMPK signalling and modified lipids in VSM and could therefore provide novel therapeutic targets in the treatment of both atherosclerosis and restenosis.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QP Physiology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Supervisor's Name: Kennedy, Dr. Simon and Spickett, Dr. Corinne M.
• Date of Award: 2013
• Depositing User: Miss Fiona H Greig
• Unique ID: glathesis:2013-4229
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 02 May 2013 15:41
• Last Modified: 02 May 2016 13:04
• URI: https://theses.gla.ac.uk/id/eprint/4229