Atherosclerosis is an inflammatory condition affecting mainly the medium sized and large muscular arteries in the vasculature. Research suggests that the role of statins as a cholesterol lowering agent is only one of their many pharmacological purposes, and that they can also be used in the treatment of inflammatory conditions such as atherosclerosis. A lot of funding has gone into this area of research as it’s predicted that in the next 15 years, it is expected that cardiovascular related events are going to be the main cause of death worldwide. Thus there is a greater need to consider novel strategies in management of cardiovascular diseases such as atherosclerosis. In the course of this essay I will attempt to describe how and why atherosclerosis is an inflammatory condition and how statins can be exploited as anti inflammatory agents in reducing the overall cardiovascular risk associated with the disease.
There is a lot of laminar blood flow through the medium sized and large arteries in the vasculature which are the prime positions for atherosclerotic plaques to grow, making the blood flow more turbulent. This leads to the build up of ischemic tissue in organs where blood flow becomes limited leading to major vascular events as a consequence. The composition of this atheroma is the first indication that the disease is of an inflammatory origin as it matches that expected at the intermediate phase of injury. Also, as seen in other inflammatory states, monocytes are attracted to the site of inflamed tissue and differentiate into macrophages. This leads to an increase in production of inflammatory cytokines and an upregulation in toll like receptors.
The plaque is largely made up of macrophages, mast cells, T cells, fibrin, collagen and platelets aggregates which indicate that the immune system has been activated to produce an inflammatory response to the insult. It is now also evident that the actual stenosis is less of a contributing factor to ischemia and that it is more of a result of the activation of plaque content, eg, macrophage and mast cells, which elicits the prothrombotic and procoagulant factors involved in thrombus formation.
The role of cholesterol in plaque formation is considerable as macrophages found in the plaque composition are heavily saturated with cholesterol ester giving them their name, foam cells. Additionally, there is a lot more LDL in the circulation which has been proven to be pro inflammatory and is raised in atherosclerosis. Raised LDL in it self is a big contributing factor to the formation of foam cells as the LDL becomes oxidised and reduces de-novo synthesis of LDL receptors on endothelial cells and macrophages. Running parallel to this, CD34 scavenger receptors on these cells become unregulated so macrophages and endothelial cells engulf cholesterol and cholesterol esters in an uncontrolled manner leading to the formation of foam cells. These then set off a series of events leading to more foam cell production and plaque formation. This illustrates the important role cholesterol has in worsening the inflammatory processes involved in atherosclerosis thus foregrounding the need of statins to utilise their lipid and non lipid pharmacological mechanisms involved in cholesterol lowering as well as controlling the inflammation.
There is a lot of evidence from experiments which link the involvement of cholesterol and inflammation in atherosclerosis. There is evidence which suggests that the presence of cholesterol results in an over expression of cell adhesion molecules, eg VCAM-1, ICAM-1 and E-selectin. Also, increased release of cytokines such as MCP-1 within the plaque as well as macrophages TNF-alpha, IFN-gamma and IL-1 which is all consistent with the inflammatory process. Additionally, mast cells are attracted and degranulated at the site of plaque formation. Other experimental evidence also shows that when cholesterol fed rats are treated with immunosuppressants; there is a reduction in the atherosclerosis. There is research into the possibility of there being some angiogenesis in the area which is consistent with the proliferative phase of repair involving the immune system. All of the above illustrates, with evidence, the inflammatory origins of atherosclerosis.
Infectious agents are also associated with activating the immune system to produce a pro inflammatory response to a foreign organism. There is further evidence which illustrates that this is also true for atherosclerosis. There have been suggestions which say that infectious agents such as Chlamydia pneumoniae damage the endothelial cells in the same way as cholesterol. Infection with this organism can cause increased cell activation and expression of adhesion molecules as well as programmed cell death at site of damage. Also, there is increased cytokine expression in smooth muscle cells and the increased size of cells correlates to the neointimal thickening (plaque) associated with the disease. Overall, this leads to the recruitment and activation of immune cells such as leucocytes which are a major contributor to the inflammatory process. It was also shown through experimental models, that this infection causing the plaque formation can be treated by azithromycin which is a well established immunosuppressant. All this evidence again foregrounds the strong correlation of inflammation in atherosclerosis.
Now that we have established that atherosclerosis is indeed an inflammatory condition which can be exacerbated by high cholesterol and infection, the treatment strategy should therefore involve the use of statins for their cholesterol lowering and non lipid properties allowing them to be effective in resolving the inflammation.
The conventional role of statins is the inhibition of HMG-CoA reductase enzyme which intern stops all the enzymatic steps occurring downstream of this enzyme to ultimately reducing hepatic cholesterol production. This leads to the inhibitory effect cholesterol has on LDL receptor synthesis being lifted so more receptors are synthesised leading to a greater uptake of cholesterol from the circulation thus lowering overall blood cholesterol levels. There is a lot of novel evidence suggesting the benefits of statins occurring before blood cholesterol reduction which illustrates that some other process must be involved. Apart from the conventional HMG-CoA reduction, statins also have non lipid related activity. They inhibit the production of mevalonic acid and isoprenoid metabolites which accounts for the apparent immunosuppressant activity of statins in atherosclerosis. In the case of inflammatory diseases, statins can also reduce smooth muscle proliferation, reduce over expression of cell adhesion molecules, reduce infiltration of macrophage and T cells to site of damage, inhibit antigen dependant T cell activation and reduce other inflammatory mediators such as IL-6, TNF alpha, C reactive protein and INF-gamma. Some studies have also shown the action of statins in vivo when an small experimental amount of 2ng/kg of LPS from E coli was injected into volunteers taking simvastatin or a placebo. The results of this study illustrated the non lipid effects of statins in response to insult as there was no change in blood TNFalpha in the group taking the statin which shows that statins have a role in affecting the body’s immune response to external insult. This clearly foregrounds the roles of lipid and non lipid mechanisms of action of statins in reducing serious outcomes related to the occurrences of cardiovascular events.
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In conclusion, it is clear from experimental evidence that atherosclerosis has been identified as an inflammatory disease. There is significant information to support the notion of using statins in a clinical setting for their lipid and non lipid effects to aid the over all reduction in the atherosclerosis and the role it has in activating an immune response. Therefore, statins can be used for their pleiotropic effects in inflammatory disease such as atherosclerosis to help alleviate the body of the inflammatory response related to the condition.
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