This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.
Heart disease is the most common cause of death in the UK. One of the most common conditions that can lead onto a heart attack is atherosclerosis. Atherosclerosis is a chronic inflammatory disease and affects arterial walls mainly in the large and medium sized arteries. During the process of atherogenesis the smooth muscle cells in the arterial walls thicken due to inflammatory responses and also by the deposit of fatty lipids. The formation of these plaques will lead to an increase in pressure within the arteries and in the event of a plaque rupturing this could lead to heart attacks or strokes. Though there are multiple factors that can contribute to atherosclerosis including genetic and environmental, one of the most determinant factor is the level of cholesterol within the blood serum. It has been shown an increase in serum cholesterol alone can cause atherosclerosis in humans and other animal models.
Low density lipoproteins
Figure 1. Ioannou, Y.A (2001)1 Structure of Lipoproteins a) Structure of a low density lipoprotein consists of an outer membrane composed of 22% phospholipids, 8% free cholesterol and also 22% of apolipoprotein B-100. LDL are 20-25mm in length, in comparison to HDL (b) they are much smaller in size and also contain half the amount of cholesterol esters inside the hydrophobic core. High density Lipoproteins also express a variety of apolipoproteins on the outer membrane, one of them apolipoprotein A is involved in reverse cholesterol transport.
Lipoproteins are important for the transport of serum cholesterol, since cholesterol is extremely hydrophobic and insoluble they are transported in complex with lipoproteins to cells and tissues. There are 5 main classes of lipoproteins; chylomicrons, very low density lipoproteins (VLDL), intermediate density lipoproteins (ILDL), low density lipoproteins (LDL) and high density lipoproteins (HDL). Chylomicrons and VLDL are rich in triglycerides; they are secreted from the intestine and liver respectively. These lipoproteins undergo lipolysis allowing the release of fatty acids to be delivered to tissues. VLDL are further metabolised with the removal of more triglycerides by lipoprotein lipase and also the removal of certain apolipoproteins, where it can then form the more stable LDL. LDL is perceived as the bad cholesterol since it has been shown that an increase of plasma LDL cholesterol is closely correlated to an increase in heart disease. Within the hydrophobic core of LDL it is composed of triglycerides and also cholesterol esters, while the outer membrane of LDL is composed of phospholipids, free cholesterol and also apolipoprotein B100 (ApoB-100) (fig 1a).
ApoB-100 is the only apolipoprotein found in LDLs and is required for binding onto LDL receptors. One of the main roles of LDL is the transport of cholesterol to peripheral tissues, in humans LDL is the main way cholesterol is transported. The LDL receptors are found in clathrin coated pits, so once LDL is bound onto the receptor through the interaction of ApoB-100 this mediates endocytosis into the cell. Once inside the cell LDL dissociates from the LDL receptor where it can then be degraded into cholesterol or other amino acids as an energy source (2).
High density lipoproteins
HDL in contrast to LDL is termed as the "good" cholesterol, as it contains a lot of anti-atherogenic properties. The outer surface of HDL cholesterol is similar to LDL containing phospholipids and free cholesterol. One of the main differences between HDL and LDL is that HDL has several types of apolipoproteins on the surface instead of one. Within the hydrophobic core triglycerides and cholesterol esters are present, but in comparison to LDL, HDL contains only half the amount of cholesterol esters in the core and is a lot smaller (fig 1b). There are also various subtypes within HDL that differ in size mainly due to the varying quantity of apolipoproteins present on the outer surface and also the percentage of cholesterol esters within the core particle.
The main apolipoprotein present in HDL particles is apolipoprotein A-1 (apo A-1), this particular apolipoprotein plays an important role in reverse cholesterol transport in peripheral tissues and macrophages. Through passive diffusion, interaction with the adenosine triphosphate-binding cassette transporter A1 (ABCA1) and through the scavenger receptor B1, cholesterol is transported out of peripheral cells. In the case of ABCA1, apo A-1 accepts the free cholesterol forming pre-Î² HDL, this free cholesterol is then converted to cholesterol esters by lecithin cholesterol acyltransferase (LCAT), this esterfication process forms the spherical Î±-HDL that is able to transport the excess cholesterol and bind onto scavenger receptor B1 (SR-B1) expressed by hepatocytes. SR-B1 promotes selective lipid uptake in the liver where the free cholesterol and cholesterol esters are removed from HDL and excreted as bile (fig2). In mouse models they have shown SR-B1 has a role in maintaining the homoeostasis of HDL. An overexpression of SR-B1 leads to the depletion of plasma HDL through an increase in selective uptake by the liver and also an increase of secretion of biliary cholesterol (3), while downregulation of SR-B1 through gene targeting in mice leads to an increase in plasma HDL (4). HDL can also be metabolised by cholesteryl ester transfer protein (CETP), this involves the transfer of cholesterol esters in HDL to other rich triglyceride-lipoproteins such as VLDL and LDL, where it will be eventually removed by LDL receptors.
Figure 2. Pajukanta.P (2004)5 Reverse cholesterol transport. The excess free cholesterol is transported out of macrophages through the interaction of ABCA1 and the apo A-1 on HDL. The free cholesterol is transported to the liver where SRB1 receptors on hepatocytes will take up the HDL particle and remove the free cholesterol (FC) and cholesterol esters (CE) and excrete them through bile. The LCAT plays a role in converting FC to CE to form the mature HDL particle.
LDL in atherogenesis
Early induction of atherogenesis
LDL can contribute to the formation of atherosclerotic plaques, this process involves LDL cholesterol diffusing through the endothelium of the artery and entering into the intima. Once it reaches into the inner-most layer of the artery it can interact and bind to proteoglycans, which makes the LDL particle more bulky trapping it within the intima (6). The trapped population of LDL is modified becoming oxidised by oxygen radicals and enzymes. Within animal models of atherosclerosis it has been shown that the increasing levels of cholesterol in the intima is also correlated to inflammation, the inflammation leads to the expression of leukocyte adhesion molecules on endothelial cells (7). With the expression of E-selectin on the cells it allows monocytes to tether onto the endothelium and roll on the surface to form a firm adhesion aided by vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1). Expression of VCAM-1 in particular can be enhanced through lysophosphatidylcholine a lipid found in oxidised LDL, this helps by promoting the release of chemokines that aid in atherogenesis (8). The adherence of monocytes on the cell surface is one of the early stages of induction in arteriosclerosis. When monocytes and also T-cells bind onto the endothelial cells expressing VCAM-1 and in the presence of the cytokine macrophage chemoattractant protein-1 (MCP-1), they can then migrate into the arterial intima. The endothelial cells and the smooth muscle cells then express a macrophage colony-stimulating factor (M-CSF) which enables the monocytes to differentiate into macrophages (9).
Oxidised LDL and macrophages
Macrophages play an important role in atherogenesis especially the expression of scavenger receptors and also toll-like receptors on their surface. The scavenger receptors allow the uptake of oxidized LDL leading to the formation of lipid-laden macrophages (foam cells). Fatty streaks are formed from the foam cells that are initially harmless, but can over a period of time form mature atherosclerotic plaques (artheroma). Macrophages that express the toll-like receptors are associated with eliciting inflammatory responses, increasing evidence show that oxidised LDLs can interact with these receptors and directly initiate an inflammatory response (10). Upon inflammation, cytokines that have pro-arthosclerotic properties and growth factors are secreted by the leukocytes and endothelial cells, further promoting atherogenesis.
Figure 3. Li, A.C & Glass C.K (2002)11 Monocyte adhesion and migration. In atherosclerosis endothelial cells express leukocyte adhesion molecules. Circulating monocytes tether onto cells expressing E-selectin where it then rolls on the surface forming a firm adhesion aided by VCAM-1 and ICAM-1. M-CSF stimulates the monocyte to differentiate into macrophages.
T-cells and oxidised LDL
It has also been implicated that T-cells can also contribute to atherogenesis, antigens that internalise oxidised LDL express components of these particles on the cell surface. There are a subset of T-cells that can recognise these antigens and have coincidently been found to be concentrated in plaques and also in the blood of atherosclerotic patients and animal models (12). These T-cells only recognise oxidised LDL and do not react to normal LDL components and usually carry characteristics of type 1 helper T-cells that are known to stimulate pro-atherosclerotic processes. One of the cytokines produced by oxidised-reactive T-cells are interferon-Î³ it can promote macrophage activation and lead to the increase of pro-inflammatory cytokines as well as an increase of nitric oxide production that can form reactive oxygen species and modify LDL(13). Interferon-Î³ has also been known to inhibit smooth muscle cell (14) and endothelial cell proliferation (15) that can lead to a decrease of collagen surrounding the atherosclerotic plaques resulting in ruptures and thrombosis (16).
HDL in atherogenesis
HDL carries a lot of properties that can help protect against atherogenesis, it can act as an antioxidant by inhibiting the formation of oxidised LDL such that atherogenic effects can't be initiated. HDL can prevent the formation of oxidised LDL by using Apo-1 and other enzymes present in HDL such as paraoxonase to hydrolyze oxidised lipids as soon as they're made. With the decreased amount of oxidised lipids there would be a less likely chance of the formation of oxidised LDL. HDL can also decrease levels of VCAM-1 by inhibiting the production of cytokines such as tumour-necrosis factor (TNF) and interleukin-1 (17), the inhibition of these factors will reduce the expression of VCAM-1 resulting in a decrease of monocytes adhering to the endothelium and thereby reduce atherosclerotic plaque formations.
Although HDL can have antioxidant properties under some conditions it can also become pro-oxidant. Evidence provided in mice showed that tyrosyl radical oxidation of HDL can help increase the efflux of cholesterol and also inhibit lesions in the aorta (18). When HDL is further oxidised or nitrated, an opposing effect is seen. HDL can become modified when nitric oxide produced by the endothelial cells comes into contact with myeloperoxidase produced by phagocytic cells. The myeloperoxidase results in the production of oxygen species derived from nitric oxide that can induce oxidative nitration within atheromas (19). This is an important factor since it was discovered that Apo-A1 is a target for myeloperoxidase and when it becomes oxidized or nitrated this impairs the interaction with ABCA1, therefore resulting in the disruption of cholesterol transport. It has also been noted a mutation in ABCA1 associated with Tangier's disease results in deficiency of HDL, leading to cholesterol build up in these cells forming foam cells and individuals suffering from this disease seem to go through accelerated atherosclerosis (20).
HDL and eNOS
Recently it has been implicated that the interaction of HDL with SR-B1 may act on endothelial cells to release endothelial nitric oxide synthase (eNOS) (21), evidence suggest oestrogen and lysophospholipids; components of HDL cholesterol, contribute to activate eNOS, that can cause vasorelaxation and essentially decrease the blood pressure in the vessels reducing the chance of aortic lesions. Though it is still unknown the exact mechanism eNOS has in atherogenesis, in many in vitro studies it has been shown the production of nitric oxide from eNOS has anti-atherogenic properties such as inhibiting leukocyte adhesion molecules and platelet aggregation. Experiments carried in mouse models varying the concentration of eNOS has so far been contradictory, atherosclerotic animal models treated with L-arginine a substrate for eNOS showed an inhibition of atherosclerotic lesion (22), while in contrast animal models treated with a NOS inhibitor L-NAME showed an acceleration of atherosclerotic lesion (23). It is hypothesised that perhaps under some circumstances such as hyperlipidaemia eNOS could contribute to the formation of oxidised LDL (24).
Atherosclerosis is a multifactorial disease, there are many risk factors that have been associated with atherosclerosis some which include age, sex, hypertension and one of the best characterised is hyperlipidaemia. As we know elevated LDL and low HDL cholesterol has been strongly associated with atherosclerosis, more importantly the role of oxidised LDL plays a significant role in the progression of atherogenesis. These lipoproteins can act on many different targets that produce pro-atherosclerotic factors. Although we know a great deal from studying animal models of atherosclerosis a problem still remains whether or not the findings will also apply to humans. Even so we can see that the progression of atherosclerosis is extremely complicated and is not caused by one factor alone, looking at the effects of oxidised LDL in atherosclerosis has already revealed multiple events that can occur which all contribute to atherogenesis. By understanding more about the events and factors that help at each stage of progression in atherogenesis, new drug targets can be developed to help combat the increasing problem of cardiovascular disease.