Current Research Understanding In The Pathogenesis Of Atherosclerosis Biology Essay

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"Atherosclerosis is a chronic multifocal smouldering immunoinflammatory disease of medium-sized and large arteries fuelled by lipids." (Falk 2006 7-12) [1]. In other words, atherosclerosis is the hardening of medium and large sized arteries by the build up of plaque and /or atheromas (lipid containing plaques) causing them to lose elasticity. Plaque is a general name for the combinations of cholesterol, fatty substances, fibrin, cellular waste products and calcium. It is known as one of the most underlying frequent causes of coronary heart diseases; including coronary artery disease, carotid artery disease and peripheral arterial disease. The most destructive consequence of atherosclerosis is superimposed thrombosis and its ability of causing myocardial infarction (heart attack) and stroke which in some unfortunate cases leads to death.

In spite of this atherosclerosis as a whole is not fully understood and there are only merely suggestions and glimpses into the causes and reasons behind this deadly disease that seems to start to develop at such a young age, yet only goes onto develop and cause further health problems in some people.

In this essay I will be looking at this research and suggestions in order to somewhat summarise and combine different research in order to develop a general understanding into "Current research and understanding in the pathogenesis of atherosclerosis".

2. Outcomes of Atherosclerosis

Atherosclerosis is an progressive disease, in which can start to develop at a very young age, however the effects do not tend to show up until much later in life and usually not until a health related issue starts to come to light.

Research suggests that atherosclerosis starts with damage to the innermost-layer of medium and large artery walls (the endothelium), because of this damage; cholesterol, fatty substances, fibrin, cellular waste products, calcium and other substances are deposited on the wall in order to help repair them. Over time these "plaques" begin to stimulate the artery wall cells to produce other substances and in turn more cells develop and fat builds up in and around the plaque and cells, all these elements start to build up together and eventually harden and thicken the endothelium in of the arteries.

This causes the lumen of coronary arteries to decrease in size and therefore blood flow and oxygen supply become limited, this decrease in blood and oxygen supply can cause stable angina (chest pain), shortness of breath as well heart attacks.

Another fatal outcome of the plaques build up is it becoming fragile and rupturing this can block blood flow of the coronary arteries to the heart as well as flaking off and travelling through the blood that feeds other parts of the body "embolism". Decreasing/ blocking blood flow to the heart causes heart attacks whilst lack of oxygen to the brain will cause a stroke. In a less fatal situation, if the flakes of plaque block blood flow to the limbs it can cause difficulty in movement and gangrene.

3. The role of Lipoproteins in the body and LDL's role in plaque build up

Nethertheless the above is only a suggestion of how/ or what causes Atherosclerosis.

Lipids such as triglycerides and cholesterol travel around the body via lipoproteins and there are 5 lipoprotein groups in the body in which do this; chylomicrons, very low-density lipoproteins (VLDL) intermediate density lipoproteins (IDL), Low-Density lipoproteins (LDL) and High-Density Lipoproteins (HDL). It has been understood is that atherogenic lipoproteins are what aid the disease to compel and those Low-density lipoproteins (LDL) more commonly known as "Bad cholesterol" are the responsible lipoproteins for this. High-density lipoproteins (HDL) or "Good cholesterol" as well as apoA-I (HDL's apolipoprotein) have been shown to prevent it.

The difference between the two is simple; Cholesterol in itself is not bad, it's the lipoprotein that it attaches itself that controls the fate of that cholesterol molecule. If it attaches to an HDL, the cholesterol is taken to the liver in order to be disposed of from the body; If attached to an LDL molecule although its original role in the body is not of harmful intent, it's original purpose being that when cholesterol is needed by a cell, the cell synthesizes LDL receptors onto the plasma membrane, these continue to diffuse until they attach to a caveolae covered in a protein called clatherin. Free LDL molecules that are travelling through the bloodstream attach themselves to these receptors and the clatherin-caveolae forms vesicles and engulf them into the cell. Post caveolae discarding of this outer clatherin layer LDL and receptors enter endosomes, cholesterol is hydrolyzed and the LDL receptors return to the plasma membrane.

The harm comes from where this cholesterol is being circulated around the blood stream by LDL waiting to be requested by LDL receptors, profoundly glycosylated glycoproteins (proteoglycans) hold these LDL particles into the endothelium of the artery (even more so if they have been oxidized) and in defence of this "attack" macrophages engulf these LDL particles into the cell and over time builds up causing plaque.

4. Risk Factors

Also recognized is what helps to increase the risk to it. It has been found that hypertension, diabetes, obesity, smoking, male gender, stress, high cholesterol, being aerobically unfit, having certain chemical markers indicating ongoing inflammation all increase and hasten up atherosclerosis and that exercise, alcohol and being female help to protect against the disease.

The way in which the factors mentioned above compel the disease is unknown, but according to the Journal of the American College of Cardiology the following two suggestions have been made;

"They may either increase atherogenicity of LDL (e.g. particle size, number, and composition) or increase the susceptibility of the arterial wall (e.g. permeability, glycation, inflammation and so on)." (Falk 2006 7-12) [2]

In simple terms it is a possibility that they either increase factors of the LDL's particle for instance decreasing particle size or increasing their amount so that their formation on to the endothelium is changed (increased) or they change the walls of the arteries so that they become more prone to the LDL's building up upon them, whether that means them becoming more inflamed so the endothelium is more frequently damaged and thus in need of repair.

5. T-Cells and their role in Atherosclerosis

Immune systems which rely on the activation of macrophages, cytokines release, natural killer cells and cytotoxic T-lymphocytes rather than antibodies are referred to as cell-mediated immunity. Cell-mediated immunity occurs when a cell is being attacked and they send an appropriate respond to this which activates the above to destroy/engulf the attacker. (This also describes the process involving LDL and macrophages referred to previously.)T-Lymphocytes also referred to as T-Cells are a prime example of this.

T Cells and their role in atherosclerosis are becoming increasingly understood as they become a rising part of research in atherosclerosis.

Researchers have found that atheromas contain a high content of accumulated white blood cells, mainly macrophages and T-lymphocytes (T-Cells) that have engulfed oxidised LDL. Like macrophages, when the arterial wall is being attacked (in this case by the oxidised LDL being held to the artery wall by proteoglycans) T-Cells Receptors act in response to this so T-Cells are activated (T-Cells are easily identified as they are the only lymphocyte that uses a receptor).

Exploration has found and understood that:

"The net effect of a deficiency in both T and B cells is a 40% to 80% reduction in atherosclerotic lesion development". (Hansson GK, Libby P 2006 508-519)[3]

T-Cells are divided into 6 subcategories: T-Helper Cells, Cytotoxic T-Cells, Memory T-Cells, Regulatory T-Cells, Natural Killer T-Cells and γδ T-Cells; these of which divide themselves also in to subcategories. T-Helper cells (Th Cells) alone have no properties in which to destroy attacking cells, but by expressing their CD4 protein on their surface (also giving them the name CD4+T-Cells) they maximise the immune system by activating other T-Cells (namely Cytotoxic T-Cells and macrophages) by expressing their CD4 protein on their surface (also giving them the name CD4+T-Cells). Th Cells themselves however, are activated by Antigen Presenting Cells (APC) which expresses "major histocompatibility complex (MHP) class II" they then go on to multiply and then secrete cytokines.

"CD4+ T cells can be subdivided into three helper T cell (Th) subpopulations (Th1, Th2 and Th3) due to different cytokine secretion patterns that are particularly distinct in mice." (Mosmann TR, Sad S.1996 138-46) [4]

Each of the three having their own responsibilities:

"Th1 cells activate macrophages and initiate inflammation" ( X. Zhou 2003 287-291) [5]

namely by producing tumour necrosis factor (TNF)-α, IFN-γ, interleukin (IL)-2 and lymphototoxin.

"Th2 cells promote allergy and are effective in helping B cells to develop into antibody-producing cells ." ( X. Zhou 2003 287-291) [6]

these secrete interleukin-4, IL-5, IL-10 and IL-13. Whereas Th3 secretes TGF-β, Th1 and Th2 have a counter-action that suppresses one another, whereas Th3 curbs Th1 response development.

Research experiments involved into the role of Th1 in the increase of atherosclerotic plaques have involved the use of mouse models (murine models), one experiment in particular conducted by George J et al [7] involved young immunodeficient atherosclerotic apoE-/-scid/scid mice having CD4+ T Cells from older apoE-/- mice transferred into them, 12 weeks later the mice had atherosclerosis levels as high as the immunocompetent ones. This experiment and many like it have found that:

"Most CD4+T cells of murine and human atherosclerotic plaques are of the Th1 cell type, producing interleukin-2 and interferon γ; and several consistent experimental studies have clearly shown a critical pathogenic role for Th1-mediated response in atherosclerosis." (Mallat 2007 113-118) [8].

6. Heat Shock Proteins (HSP) and atherosclerosis

Heat shock proteins which are present in both eukaryotic and prokaryotic cells are only expressed in times of rapid temperature increase and stress (including pH change, inflammation and infection). During periods of cell stress they act as a chaperone in a sense that they bind and stabilise unstable proteins and arbitrate protein folding. Split into subcategories and named according to their molecular weight HSP's families are as follows: HSP150, HSP100, HSP90, HSP70, HSP60 and the low-molecular weight families (10, 20, 20, 40). In recent years, It has been suggested and some researchers have found HSPs in the lesions of human atherosclerosis aswellas soluble forms in the blood rather than only in cells suggesting that they could well be autoantigens, HSP60 being found as the main perpetrator of this early atherosclerosis formation, although research shows that HSP70 and HSP40 also contribute to this. HSP60s physiological function itself is to accumulate polypeptides, progress proteins across membranes and to speed up protein (un)folding, even so research shows that other that atherosclerosis it also shows involvement in schizophrenia, adjuvant/rheumatoid arthritis, systemic sclerosis and diabetes type 1.

HSPs relationship with atherosclerosis was first reported by Berberian et al [9] by looking at both human and rabbit arteries firstly concentrating on the early death of cells/tissues and lipid accumulation, he then went on to look at atherosclerosis plaque, namely macrophages and vascular smooth muscle cells within them he found concentrated HSP70 in the atheromas and that they were particularly stressed within their depths.

HSP60 itself was demonstrated as a perpetrator of atherosclerosis by Kleindienst et al10, he compared samples of carotid, aortic and small blood vessels (with small diameters). He detected that on samples of blood vessels with small diameters that he used to represent normal intima (no atheromas) HSP60s showed no detectable expressions. Whereas in all carotid and aortic vessels HSP60 was established, specifically on smooth muscle cells, the endothelium and the mononuclear cells. Thus, positive correlation was found between rigorousness of atherosclerosis in the vessels and concentration of HSP60.

How does developing research suggest that HSP60 enhances atherosclerosis? There have been many suggestions for how HSPs (HSP60) does this.

Firstly in regards to HSP's and their primary role in cell function, during periods of stress and temperature change including in that of infections (infections themselves have also been suggested to play a key function in the pathogenesis atherosclerosis). In mammals HSP60