Review of Literature

ion of a hydrogen atom from one of these double bounds results in a new radical lipid species that can readily interact with molecular O2. The resulting lipid peroxyl radical can abstract a hydrogen atom from another fatty acid yielding another radical and lipid hydroperoxide (LOOH) establishing a chain reaction. The LOOHs formed are unstable and can decompose into various species including malondialdehyde (MDA) or it can be reduced to the more stable alcohol form. As these reactions progress, ionic channels may be affected, membrane transport proteins or enzymes may be inactivated or the lipid bilayer itself may become more permeable thereby disrupting ion homeostasis. In addition, some of the oxidized fatty acid REVIEW OF LITERATURE 10 species such as the isoprostanes or hydroperoxides, have biologic activity and an ability to affect signaling pathways. 39 Lipid Metabolism Serum cholesterol is transported in the circulation by several lipoproteins which are specialized in transporting dietary and endogenously produced lipids. The dietary lipids are transported by chylomicrons and the endogenous lipid transport is carried out by very low density lipoproteins (VLDL), LDL and high density lipoproteins (HDL). Triglyceride (TG) rich VLDL particles are synthesized by the liver and contain apolipoprotein B (apoB) and apolipoprotein E (apoE). 44 After TG removal in the peripheral tissues, such as adipose tissue and muscles, a portion of the remaining VLDL remnants progressively changes into lipoproteins with intermediate density and finally to cholesterol-rich LDL. VLDL and intermediate density lipoprotein (IDL) have a short half-life and are removed from the circulation within hours, whereas the LDL particles have a rather long life and circulate in the blood for about two days before they are cleared. 45 Modification of LDL lipids and apoB increases its effects and enhances the inflammatory process in atherosclerosis. 46 LDL can be oxidized in the subendothelial space and depending on the degree of oxidation, minimally modified LDL and fully oxidized LDL is formed. 47 Modified LDL participates in the development of atherosclerosis by increasing the monocyte recruitment to the vessel wall and by foam cell formation. 48 Oxidative Modification of LDL in Atherosclerosis Oxidized-LDL: The term ox-LDL was traditionally used to describe the LDL modified by exposure to copper ions which catalyzed lipid peroxidation. Nowadays, the term ox-LDL has been extended to additionally describe several chemical, biological and immunological entities such as the measurement of conjugated dienes, susceptibility of LDL to oxidation and autoantibodies against various epitopes of oxLDL. 49 Oxidation of LDL may involve fragmentation of its constituent molecules, including cholesterol, fatty acids, antioxidants and apoB. Therefore, ox-LDL does not describe only a single particle but also a spectrum of oxidized particles in different stages. 50 REVIEW OF LITERATURE 11 Susceptibility of LDL to oxidation: There are several intrinsic properties of LDL that can affect its susceptibility to oxidation, such as the antioxidant content, fatty acid composition and LDL particle size. 51 There are contradictory studies on the HDL ability to protect LDL from oxidation and it has been suggested that HDL particles may be more susceptible to oxidation than LDL. 52 The antioxidant status of LDL and plasma are important determinants of the susceptibility of LDL to peroxidation. 39 In addition, the LDL size and density also influence the extent of oxidation and small dense LDL is more susceptible to oxidation than large buoyant LDL. 40 In plasma circulation, LDL is protected from oxidation by the presence of antioxidants, but in the arterial wall the LDL particle is a more vulnerable subject of oxidation. Typically, the oxidation takes place in a microenvironment where the number of antioxidants is low as in the vessel wall and only to a minor extent in the blood. 53 However, the exact mechanisms of this process are not yet fully understood. 54 The LDL particles undergo a series of modifications such as nonenzymatic glycation, enzymatic degradation and aggregation, which generates a wide spectrum of oxidation specific neo-epitopes. Oxidation involves the lipid moiety of LDL in a chain reaction mechanism. In the initial phase, free radicals preferentially attack highly oxidizable polyunsaturated fatty acids. The LDL oxidation also leads to a significant loss of cholesterol as it is converted into a range of oxysterols. The modified LDL particles and oxidized lipids are proinflammatory and trigger both humoral and cellular immune response. 55 Scavenger receptors (SRs): Oxidation-altered apoB of oxidized LDL is recognized by the macrophage SR, which is responsible for foam cell formation. Recognition of ox-LDL is related to the derivatization of lysine residues or fragmentation of apoB which leads to a net negative charge. 39 The SRs of monocyte-derived macrophages can recognize a wide range of negatively charged macromolecules, ox-LDL, damaged or apoptotic cells, and pathogenic microorganisms. In physiological conditions, SRs serve to scavenge or clean up cellular debris and other related materials as a part of the host defense. OxLDL is known to be taken up via SRs in a manner which is independent of the cholesterol-dependent LDL receptor downregulation. The unlimited accumulation of cholesterol in the macrophages eventually leads to the formation of foam cells, a cell type already involved in early atherosclerosis. 56 REVIEW OF LITERATURE 12 Proatherogenic Activities of Oxidized LDL (Ox-LDL) Ox-LDL has several proatherogenic effects such as the inhibition of eNOS, promotion of vasoconstriction and adhesion, cytokine stimulation and stimulation of platelet aggregation. 34 Ox-LDL has also been shown to upregulate vascular endothelial growth factor (VEGF) expression in macrophages and ECs through activation of peroxisome proliferator-activated receptor-γ (PPARγ) and stimulates TF and PAI-1 synthesis. 37 Ox-LDL measured directly from plasma has been reported to be independently associated with subclinical carotid artery atherosclerosis in middle-aged