Saturday, 13 June 2015

Question 4: Discuss causes, effects and treatments of atherosclerosis

*These posts are from coursework answers for my degree, but the Figures that are referred to in the text didn't scan well and have already been handed in. These long posts would probably not interest most people but if you enjoy quite in-depth reading of scientific problems then this may be for you.

Question 4: Atherosclerosis in the coronary circulation causes heart disease; discuss the causes of atherosclerosis and its effect on the cardiovascular system. How are stents used to treat atherosclerosis?


Atherosclerosis is the build-up of plaque formed primarily by white blood cells and cholesterol within the innermost membrane of an artery wall, called the tunica intima (Seeley, VanPutte, Regan and Russo, 2011, p. 725). This accumulation of plaque is a slow process, often taking years or decades to present with any symptoms, if at all, to the person suffering from it. It is important to note that oxidised low-density lipoproteins (ox-LDLs) are considered more atherogenic than native LDLs. This is agreed upon in many works, for example; Samsioe (1994), Panza, and Cannon, eds. (1999, pp. 89-92), and Kummerow, (2013). Dr. Kummerow, in particular, gives much weight to the pathological effects of oxidised cholesterols, known as oxysterols. He believes that the intake of oxysterols via fried foods, excess vegetable oils (especially partially hydrogenated vegetable oils) and cigarette smoking play a far greater role than simple dietary cholesterol. This will be a part of the original thought later on in this essay.
Schmidt (2000, p. 38), explains that as cells take in LDL cholesterol to satisfy their metabolic requirements, they begin to exhibit fewer cell membrane receptor sites for LDLs. Therefore, if a high concentration of LDL cholesterol exists in the bloodstream, then cells will take in as much as they need, down-regulate their receptor sites, and the remaining cholesterol will be free to circulate the body. This means that more of the cholesterol will be free to travel the circulatory system and become deposited in walls of blood vessels, leading to an increased risk of arterial diseases. The use of receptors on cell surface membranes in order to take in a specific molecule or nutrient is an example of receptor-mediated endocytosis (Pack, 2001, pp. 26-27). When this occurs, a vesicle is formed as the cell membrane folds inwards around the substance being received. Once the substance is safely inside of the cell, the vesicle can break-down, releasing, in this case, the LDL.
 The resultant problems associated with atherosclerotic lesions are typically due to the narrowing of blood vessels (stenosis), this decreases the available size of lumen for blood to travel through, leading to a reduction in blood supply to tissues (ischemia). There are many causes of atherosclerosis, these include: Hypercholesterolemia or dyslipidemia (particularly increased LDL [low-density lipoprotein] concentrations, but decreased levels of HDL [high-density lipoproteins that appear to offer a protective effect against plaque build-up] are also a risk factor [Carmena, Duriez and Fruchart, 2004]). Habitual cigarette smoking (Lin, et al,. 1992) has also been found as a potential factor in disease progression. Mitchell, et al. (2007, p.345) show that diabetes, elevated C-reactive protein in serum, growing older, male gender, genetic faults that produce high levels of cholesterol and family members who have suffered from atherosclerosis and its related cardiovascular incidences (more detail further on in this essay), were more likely to get the disease. Concomitant disorders also include obesity and insulin resistance (as well as type 2 diabetes), as shown by Hotamisligil (2010).
The above factors will be touched upon briefly, however a lot of this write-up will be dedicated to biochemical pathways within the body that both decrease and contribute to atherosclerosis, and how a down-regulation of antiatherogenic chemicals can lead to this disease.
Some of the more microscopic changes that occur to bring about atherosclerosis include but are not limited to the following: Monocyte and macrophage adhesion to endothelial cells, platelet aggregation, reduced endothelial nitric oxide levels, high endothelial permeability increasing the migration of lipoproteins into the walls of arteries, and increased vascular smooth muscle cell proliferation, this rapid reproduction rate greatly speeds up the aging process (Panza, and Cannon, eds., 1999, p. 44).
One of the largest factors in the occurrence and progression of atherosclerosis is the movement of lipoproteins, primarily LDLs, into the arterial wall, where they can then deposit cholesterol which can become oxidised. HDL is considered protective in this situation as it bonds to cholesterol and carries it to the liver. This is one of the main reasons why proportions of varying types of lipoproteins is an important study in these diseases, in particular, having low HDL and high LDL is considered a strong factor in the onset of atherosclerosis (American Heart Association, 2014a).
Mescher (2013, pp. 234-239) shows that the whole blood consists of approximately 1% leukocytes and platelets combined (white blood cells) which are usually inactive while circulating the body. Their activity is apparent however, when they are signalled to sites of infection, inflammation or general damage. Here they will migrate into tissues and exert (generally) appropriate action. In the case of atherosclerosis, the prime white blood cell to be considered is the monocyte, an agranulocytic blood cell that, among many other functions, modulates the concentrations of LDLs in the arterial wall, it has this capability because it is a precursor of the macrophage (an immune cell of the mononuclear [one nucleus] phagocyte system, that engulfs cellular remnants and infectious agents, among other substances and living matter). Whenever LDLs and particularly oxidised LDLs are present in the arterial wall, monocytes (a form of leukocyte) are coaxed into adherence to the endothelial cells by the presence of a protein, VCAM-1 (vascular cell adhesion molecule 1 or vascular cell adhesion protein 1, as shown by the National Center for Biotechnology Information, 2015). Without this protein, the monocyte would continue its journey around the body without stopping. Instead, the monocyte will migrate into the endothelium experiencing LDL-induced inflammation and will differentiate into a macrophage, in order to phagocytise the offending molecule and carry it away.

If this process becomes chronic, i.e. many LDLs are constantly permeating the endothelium and causing inflammation, then a high concentration of macrophages will exist within the endothelium in order to try and remove these LDLs. This accumulation of monocytes is called extravasation (Mescher, 2013, p. 245). Unfortunately, the presence of so many macrophages and resultant inflammatory response leads to disproportionate tissue damage within the artery. As the macrophages engulf lipoproteins they begin to change size and shape, and are termed “foam cells” (Oh, et al., 2012). The change in appearance is due to the high concentration of lipoproteins within the macrophages. When this occurs, the atherosclerotic lesion begins to look like a fatty streak. This point in the progression of atherosclerosis is usually not severe enough to induce significantly restricted blood flow within the artery to the point of producing symptoms, but the artery becomes more rigid and susceptible to damage.
Thus, we can see that endothelial permeability to low-density lipoproteins is a prime factor in atherosclerosis. If the endothelium did not allow LDL to move into it, then there would be no need for macrophages to enter either, possibly preventing atherosclerosis from even beginning.
As time goes on, macrophages begin to die and release chemicals that further exacerbate inflammation, leading to a greater immune response within the area. This causes more monocytes to be signalled to the vessel wall and differentiate into macrophages, furthering the progression of plaque formation. This occurs primarily between the tunica intima and tunica media (American Heart Association, 2014a). Also over time, calcium deposits build up due to poor clearance of cellular debris from these deceased cells. This is because the atherosclerotic plaque proves too great a physical barrier to facilitate their removal. Further to this, if the atherosclerotic plaque ruptures, possibly due to the high blood pressure in the artery and weak structural strength of the plaque, then a clot may form. A clot is the entrapment of blood cells, fluid and platelets by fibrin (a protein that encourages clotting).
Another name for a blood clot is coagulation, and the proteins involved in its production are called either coagulation or clotting factors, which are contained in blood plasma. Under ordinary conditions, these factors remain inactivated, however, when damage occurs to tissue, such as a weakened blood vessel in our case of atherosclerosis, the coagulation factors become more active. The initiation of clotting can occur via an extrinsic or intrinsic pathway, though both link into a later route of chemical reactions called the common pathway (Seeley, VanPutte, Regan and Russo, 2011, pp. 660-661).
The extrinsic pathway of clotting starts due to the presence of chemicals that are not contained within the bloodstream. This could be from the release of thromboplastin (other names for this chemical are factor III or tissue factor) as a result of tissue damage. If calcium ions react with thromboplastin, the result is a compound containing factor VII which can react to activate another chemical called factor X. This is the point where the common pathway begins at the end of the extrinsic pathway (Seeley, VanPutte, Regan and Russo, 2011, p. 661).
The intrinsic pathway starts off differently, with chemicals that are contained within the blood stream, such as collagen which can be exposed when blood vessels are injured. Whenever a chemical called plasma factor XII reacts with this collagen, the factor XII becomes active. Consequently, factor XI is activated, leading to stimulation of factor IX, which binds with various other molecules, such as factor VIII, phospholipids contained within platelets, and positive calcium ions. The result of this is that factor X becomes acitivated, and this is the point where the common pathway begins, just like at the end of the extrinsic pathway (Seeley, VanPutte, Regan and Russo, 2011, pp. 661-662).
At the beginning of the common pathway, prothrombinase is formed by the binding of factors X and V, along with phospholipids from platelets, and calcium ions. Prothrombinase is capable of converting a protein dissolved in plasma, called prothrombin, into thrombin, an enzyme highly important in clot formation. This enzyme produces a protein called fibrin from fibrinogen (another protein dissolved in plasma). The fibrin formed is responsible for the entrapment of platelets, blood cells and fluids that make up a blood clot. Blood clotting is a relatively rare example of positive feedback in the human body, because its presence can lead to the production of its own precursors (e.g. factor XI and prothrombinase). Vitamin K is necessary for clot formation, and its deficiency can lead to excessive bleeding (Seeley, VanPutte, Regan and Russo, 2011, p. 662).
When a clot is attached to an arterial wall it is called a thrombus. After a clot has formed and attached itself, it starts to become denser due to clot retraction. This occurs because platelets, arranged as extensions to fibrinogen (which are bonded to fibrinogen receptors on cells of the blood vessel wall), begin to contract through the use of actin and myosin filaments, effectively pulling on the fibrinogen and drawing the clot into a more compact structure. This process liberates serum (a fluid similar to plasma, but which doesn’t contain some clotting factors, as well as fibrinogen). As a result of this, the injured blood vessel is more tightly sealed up, allowing it to recover more easily, and reducing the possibility of infection (Seeley, VanPutte, Regan and Russo, 2011, p. 663).
Figure 4.1 shows the development of atherosclerotic plaque and subsequent clot formation. Here we see that the plaque itself is enough to cause significant narrowing of the blood vessel, however, due to rupture of plaque, a thrombus has started to form. This thrombus is further restricting blood flow through the artery and will be discussed further blow. The diagram also shows that the plaque is developing between the tunica intima (innermost membrane of the artery, and one that separates other tissue layers from the lumen) and the tunica media. (Seeley, VanPutte, Regan and Russo, 2011, p. 725).
A fundamental chemical involved in atherosclerosis is nitric oxide. A reading of the literature greatly brought up the antiatherogenic importance of this small, highly-reactive free radical. Its production is decreased in atherosclerosis (Panza, and Cannon, eds., 1999, p. 20) and this has a strong effect in the progression of the disease, as will be elaborated on below.
It is important to note before continuing that the following substances either inhibit nitric oxide (NO) directly, either in production (which occurs via the nitric oxide synthase enzyme), release or functional effect:
Endothelin-1, abbreviated to ET-1. This is a petide composed of 21 amino acids that is produced in the endothelium, one of its main effects is as a vasoconstrictor. ET-1 has been shown to be elevated in atherosclerosis and likely contributes to the disease. Its vasoconstriction effects are roughly a hundred times stronger than noradrenaline per unit of concentration. Oxidised low-density lipoproteins increase its release, explaining its increased production during atherosclerosis. It also attracts monocytes to atherogenic lesions because it has chemoattractant effects (Panza, and Cannon, eds., 1999, pp. 97-109).

Angiotensin II or Ang II is also implicated in the development of atherosclerosis and reduction of nitric oxide. This is a peptide hormone that also has vasoconstrictive effects. Its administration has been shown to increase the size of atherosclerotic lesions in mice deficient in apolipoprotein E (this is a molecule that breaks down lipoproteins, and without it, mice as well as humans, have a much greater risk of developing atherosclerosis, Daugherty, A., Manning, M.W., and Cassis, L.A. 2000).  Nitric oxide also inhibits the effects of Ang II in the vasculature (Toda, N., Ayajiki, K., and Okamura, T. 2007).
Asymmetrical di-methylarginine (ADMA), this is a circulating amino acid that is similar in structure to L-arginine. As l-arginine is a precursor to nitric oxide, ADMA is able to interfere with this metabolic pathway, by interacting with its components, namely the nitric oxide synthase enzyme (NOS).
NG-monomethyl-L-arginine (L-NMMA) as well as L-nitroarginine methylester (L-NAME) share a similar effect, by competing with L-arginine for the active site of the NOS enzyme (Panza,  and Cannon, eds., 1999, p. 165). This occurs because the production of nitric oxide from L-arginine results from the oxidation of the terminal containing a guanidine-nitrogen bond, which is also contained within the inhibitors mentioned above.
Implicated as well in the down-regulation of various aspects of nitric oxide are many reactive oxygen species (ROS) including the superoxide anion (O2-) and hydrogen peroxide (H2O2). This is due to the effect of these species to rapidly and chemically alter nitric oxide. Panza, and Cannon, eds. (1999, p. 134) show that the reaction between the superoxide anion and nitric oxide produces the peroxynitrite anion, a relatively stable ion compared to the particular radicals in this example of its creation. The peroxynitrite anion loses many of the qualities of nitric oxide, but retains a small ability to cause vasodilation, unfortunately it is also damaging to cells and therefore needs to be detoxified (Panza, and Cannon, eds., 1999, p. 23).
The following substances in some way enhance the effect, production or release of NO:
Estrogen, via its effect of up-regulating the eNOS enzyme (Chambliss, K.L., and Shaul, P.W. 2013). Interestingly, estrogen has also been shown to alter lipid profile in humans. Specifically, estrogen has been shown to reduce both total and LDL-cholesterol levels while raising HDL. Evidence is currently gathering which points towards an additional antiatherosclerotic effect of estrogen, namely in the inhibition of lipid oxidation, this is based on an overall review of the literature by Samsioe, 1994. As mentioned above, oxidised lipids are considered more important in the onset and progression of atherosclerosis.
L-arginine is also important (as mentioned above, L-arginine is a precursor for NO).
The peroxynitrite anion (the actual formation of this anion actually greatly reduces the effect of NO because it is formed via the reaction of nitric oxide with the superoxide anion and attenuates the vasodilatory effects of NO, however, the presence of the peroxynitrite anion itself still contributes to some of NO’s effects, this information is referenced above in the text about reactive oxygen species).
The cysteine-containing NO donor SPM-5185, as demonstrated in (Panza, and Cannon, eds., 1999, p. 22).
Finally, antioxidants such as vitamin C (in some trials), and the enzyme superoxide dismutase (SOD) as shown in (Panza, and Cannon, eds., 1999, p. 135).
When talking about nitric oxide in relation to atherosclerosis, the endothelium of arteries is the primary point of interest. Thus, the notation eNO (for endothelial nitric oxide) and eNOS (short for endothelial nitric oxide synthase) can be used interchangeably with NO and NOS for this topic.
eNO is highly important in alleviating and preventing atherosclerosis because it first of all decreases endothelial permeability. As covered previously, when the endothelium is highly permeable, more low-density lipoproteins are allowed to pass through it into the arterial wall, and this is what requires macrophage activity. In decreasing endothelial permeability, the whole onset of atherosclerosis could be abated. Much of the information regarding nitric oxide as shown above is available in the works of Panza, and Cannon, (1999) where it is backed up by hundreds of in-text citations.
The eNO radical also reduces monocyte adhesion to cells of the endothelium, seemingly by inhibiting the expression of VCAM-1. This would prevent the influx of monocytes and subsequent differentiation into macrophages, thus inhibiting foam cell occurrence. eNO also attenuates platelet aggregability, as shown by Panza, and Cannon, eds. (1999, pp. 120-122). The cohesion of platelets at the site of inflammation of endothelium can lead to a thrombosis (a clot attached to a blood vessel) that starves cells and tissue further down the vessel of oxygen. If the cells further downstream of the thrombosis are cardiac muscle cells (myocardium) then the result can range from angina to a heart attack.
This next section details the possible adverse effects associated with atherosclerosis. It is important to note that each issue may occur as both a result of the build of plaque directly, but also indirectly, as plaque formation can lead to blood clots that cause and/or exacerbate many cardiovascular incidents. As plaque builds up between the tunica intima and the lumen there is a possibility of plaque rupture. This is shown on the atherosclerosis webpage of the American Heart Association (2014b). The subsequent effect of this is that a stationary clot (thrombus) in the wall of the affected blood vessel may further reduce the size of the lumen and ability of blood to through the vessel. This can cause or contribute to all of the problems shown below, for the same reason as a gradual build-up of plaque, for it limits the blood flow to areas of the body downstream from the affected blood vessel.
Alternatively, the blood clot formed at the rupture site of plaque can dislodge from the arterial wall and become free-floating. In this case it is called an embolus and can cause an embolism (a substance that produces obstruction within a blood vessel). This can cause the same effect as a thrombus, but the embolism can float around and block a vessel located in the distal systemic circulation (Kumar, Abbas, and Fausto, 2004). This is also briefly pointed out in the work of Seeley, VanPutte, Regan and Russo, 2011, p. 663.
Angina pectoris usually presents as a pain in the chest, though it may also appear in the lower jaw, neck and possibly also the left arm or shoulder. It is caused by anaerobic respiration in the heart. It can arise from atherosclerosis due to narrowing of blood vessels within the coronary circulation. This causes restricted blood and oxygen flow to the cardiac muscle. Unable to respire aerobically but still requiring energy, the cardiac muscle cells must survive on anaerobic respiration due to hypoxic conditions. Unfortunately, this respiratory pathway causes a build-up of acidic by-products that raise acidity (and lower pH) in the affected area. This causes a pain response to be stimulated. This situation is exacerbated by any process demanding additional cardiac output, for example physical and mental stress. On the other hand, relaxation would have the opposite effect by reducing cardiac exertion. Vasodilation via chemical intervention (nitro-glycerine or free radical NO) or placement of a stent can increase the blood flow through the affected artery and improve oxygen of the cardiac muscle as well as improving the removal rate of acidic by-products of respiration. A clot could also cause this issue as a result of atherosclerotic plaque rupture. The formation of a clot in a blood vessel in this situation would further restrict blood flow through the vessel, provided that the clot doesn’t cause severe obstruction. Angina pectoris is a relatively minor condition, provided that it is only short-lasting. Normally if the blood flow is restored, there is only mild permanent damage to cardiac tissue.
Myocardial infarction (heart attack), is caused by a more lengthened condition of hypoxia (or even anoxia). In this circumstance, instead of just pain, the cardiac cells may die in large numbers in affected areas. Atherosclerosis increases the possibility of myocardial infarction because the resultant lesions can greatly reduce the size of the lumen of coronary arteries, thus increasing blood pressure and possible clot formation (thrombus). This thrombus further narrows the blood vessel and exacerbates cell hypoxia, perhaps leading to total anoxia in some areas, depending on severity. This leads to cell death in the cardiac tissue. The above information on angina pectoris and myocardial infarction can be found in the work of Seeley, VanPutte, Regan and Russo (2011), p. 686.
Stenosis can also lead to enlargement of certain regions of the heart, such as the left ventricle. Because the left ventricle is required to pump blood around the whole body via the aorta, if there is stenosis in the aorta as a result of atherosclerotic plaque, then there is increased resistance to the contraction of the left ventricle. This means that the left ventricle must work harder in order to overcome the resistance, otherwise the whole body will become affected by hypoxia due to decreased blood supply. This can lead to hypertrophy of the left ventricle, an increase in size of the muscles located here. The ventricular hypertrophy allows the left ventricle to have more contractile force and push more red blood cells through the stenosed aorta and into the systemic circulation. It was mentioned in question 2 that the arterial stenosis causes an increase in ventricular afterload which the left ventricle must overcome (Jardins, 2008, p. 210). The increased force through the aorta increases systolic pressure. This information was found from Seeley, VanPutte, Regan and Russo, 2011, Appendix G, A-34 9 a-f.
A stent can be used to treat atherosclerosis. In this case, the stent is typically made of metal and is transported into the artery which is clogged with atherosclerotic plaque. This occurs during a procedure called angioplasty in which an empty balloon is inserted via catheter into the blood vessel which has narrowed. Once inside the vessel, the balloon is inflated in order to open it up and reduce stenosis. This occurs because the pressure of the balloon is both able to forcibly widen the blood vessel and also in squeezing the atherosclerotic plaque so that it takes up less space within the lumen of the blood vessel. At this point, if the catheter also contains a stent, as it would in the case of atherosclerosis, then this stent can hold the vessel open to the extent that the balloon did. Thus, even when the inflating balloon has left the blood vessel, it stays open to the same extent via the stent. Therefore, the stent provides a more long-term ability to reduce stenosis. This has the same effect as a vasodilator in holding the blood vessel open. So far, only the mechanical properties of the stent have been touched upon. However, a stent can also produce pharmacological effects as well. This is achieved by coating the outer surface of a stent with medication which slowly releases into the arterial wall and/or blood stream. Stents that have this capacity are called drug-eluting-stents (DES). Blood which would ordinarily be forced through a narrower space in the vessel, possibly leading to a blood clot or greatly increased blood turbulence, is now free to travel through at the normal speed and pressure. This can decrease the likelihood of cardiovascular incidences, such as those covered above.  Additional lifestyle measures must also be taken however, as over time the stent itself can become clogged if the underlying cause of arterial stenosis is not removed. This process of repeated narrowing of the blood vessels after a measure has been taken to reduce it is called restenosis. This information is shown clearly on the stent webpage of the American Heart Association (2014c). Figure 4.2 shows the placement of a stent in the coronary artery. As can be seen from this diagram, the stent is made of a metal mesh and is pressing against the atherosclerotic plaque, thus opening up the lumen of this blood vessel. Once the stent has been placed via the catheter, both it and the guide wire are removed, leaving the stent to hold the artery open.
This portion of the essay is dedicated to thought not seen in work by other sources on atherosclerosis. Any relation to previous work done by any author on this topic is purely coincidental.
It is possible that some of the development of atherosclerosis is due to increased ventilation and oxidative stress during mental stress. Granted modern society has many problems when it comes to eating nutrient-depleted, high-fat foods and breathing indoor air, but with many economic factors causing significant stress and subsequent increases in respiration occurring as part of the fight-or-flight reaction, various bodily changes are likely to occur. For example, it is possible that prolonged mental stress and resultant over-breathing reduce the bodily carbon dioxide levels and inhibit the Bohr Effect, leading to an increased need for erythrocytes and a permanent shifting towards elevated ventilation. This would also increase the level of oxygen dissolved in blood plasma, as a result of air pressure within the lung during inspiration. From this, more oxygen would travel through the bloodstream, and cause oxidative stress throughout the body. This would exacerbate the peroxidation of lipoproteins and oxysterol production, thus contributing towards atherosclerosis.
Another possible related mechanism for atherosclerosis is mouth-breathing. Because nitric oxide is also produced within the nose, nose-breathing may also allow significant quantities of nitric oxide to diffuse into the blood stream, which may perhaps be unlikely given that it is a highly-reactive free radical, but it could bind to haemoglobin, as opposed to travelling freely, see Seeley, VanPutte, Regan and Russo, (2011) p. 653. The aforementioned reaction between the superoxide anion and nitric oxide would readily result, decreasing the amount of oxygen available for lipid peroxidation and subsequent atherosclerotic plaque formation in blood vessels. Research into the use of cancer cell growth inhibitors brought up the topic of iron-mediated reactive oxygen species production (Galaris, and Pantopoulos, 2008). This abstract points towards iron accumulation as being a cause of reactive oxygen species formation with toxic effects. It is possible that this could further add to lipid peroxidation, with formation of oxidised LDLs capable of atherogenesis.

Question 4 References:
American Heart Association, 2014a. Cholesterol and CAD. [online] Available at: <> [Accessed 4 April 2015].

American Heart Association, 2014b. Atherosclerosis. [online] Available at: <> [Accessed 4 April 2015].

American Heart Association, 2014c. Stent. [online] Available at: <> [Accessed 4 April 2015].

Carmena, R., Duriez, P., and Fruchart, J.C., 2004. Atherosclerosis: Evolving Vascular Biology and Clinical Implications, Cicrulation, [online] Available at: <> [Accessed 1 April 2015].

Chambliss, K.L., and Shaul, P.W., 2013. Estrogen Modulation of Endothelial Nitric Oxide Synthase. Endocrine Reviews. [online] Available at: <> [Accessed 4 April 2015].
Daugherty, A., Manning, M.W., and Cassis, L.A., 2000. Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. The Journal of Clinical Investigation. [online] Available at: <> [Accessed 4 April 2015].
Galaris, D., and Pantopoulos, K., 2008. Oxidative Stress and Iron Homeostasis: Mechanistic and Health Aspects. Critical Reviews in Clinical Laboratory Sciences. [e-journal] 45(1), pp.1-23, Abstract only. Available through: Informa Healthcare website <> [Accessed 7 April 2015].
Hotamisligil, G.S., 2010. Endoplasmic reticulum stress and atherosclerosis. Nature Medicine [online] Available at: <> [Accessed 4 April 2015].

Kumar V., Abbas A.K., and Fausto N., 2004. Robbins & Cotran Pathologic Basis of Disease: With STUDENT CONSULT Online Access. 7th ed. Philadelphia: Saunders.

Kummerow, F.A., 2013. Clinical Lipidology. Future Medicine. [online] Available at: <> [Accessed 4 April 2015].
Lin S.J., Hong C.Y., Chang M.S., Chiang B.N. and Chien S., 1992. Long-term nicotine exposure increases aortic endothelial cell death and enhances transendothelial macromolecular transport in rats. Arteriosclerosis, Thrombosis, and Vascular Biology [online]. Available at: <> [Accessed 1 April 2015].

Mescher, A.L., 2013. Junqueira’s Basic Histology Text & Atlas, 13th ed. China: The McGraw-Hill Companies.
Mitchell, R.S., Kumar, V., Abbas, A.K., and Fausto, N., 2007. Robbins Basic Pathology: With STUDENT CONSULT Online Access. 8th ed. Philadelphia: Saunders.

National Centre for Biotechnology Information, 2015. VCAM1 vascular cell adhesion molecule 1 [Homo sapiens (human)] [online] Available at: <> [Accessed 4 April 2015].

Oh, J., Riek, A.E., Weng, S., Petty, M., Kim, D., Colonna, M., Cella, M. and Mizrachi, C.B., 2012. Endoplasmic Reticulum Stress Controls M2 Macrophage Differentiation and Foam Cell Formation. The Journal of Biological Chemistry, [online] Available at: <> [Accessed 4 April 2015].

Pack, P.E., 2001.  Anatomy and Physiology, Hoboken, NJ: Wiley Publishing, Inc.
Panza, J.A. and Cannon, R.O., eds., 1999. Endothelium, Nitric Oxide, and Atherosclerosis. Armonk, NY: Futura Publishing Company, Inc.

Samsioe, G., 1994. Cardioprotection by estrogens: mechanisms of action—the lipids. [online] Available at: <> [Accessed 4 April 2015].
Seeley, R.R, VanPutte, C.L., Regan, J. and Russo, A.F., 2011. Seeley’s Anatomy & Physiology, 9th ed. New York, NY: McGraw-Hill.
Schmidt, F., 2000. Biochemistry II, New York, NY: Wiley Publishing, Inc.
Toda, N., Ayajiki, K., and Okamura, T. 2007. Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation. Pharmacological Reviews. [online] Available at: <> [Accessed 4 April 2015].

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