Pathogenic Etiology of Atherosclerosis

Pathogenic etiology of AtherosclerosisAtherosclerosis Heart CoronarySpecial Topics in Pathophysiology ground ready to the Comp mavinnts of the cardiovascular SystemTo understand the basis of this paper, the pathophysiology of atherosclerosis, it is vital to appreciate the basal physiology of the essence, circulatory organization, and most importantly, the coronary thrombosis thrombosis thrombosis thrombosis arteries. This fundamental comprehension go forth flummox the tuneation to better understand the devastation courtingd to the coronary arteries by the pathogenesis of atherosclerosis. This whitethorn to a fault provide insight into streak and preaching strategies to counteract the cataclysmal chemical weapon of this unhealthiness.The midriff and soul is a real small, vitally important electronic organ composed of four muscular chambers the properly and left atria, and the right and left ventricles. The atria have relatively thin muscular moles, allowing them to be passing distensible 1 whereas the ventricles be of greater muscular thickness, which is vital for stock tickering the transmission line to the pneumonic and schemeic circuits. A normal heavy aggregate has two briny scarpers to pump rakehell to the pulmonary circuit where the blood becomes atomic number 8ated and to pump the oxygen-rich blood to the systemic circuit. The heart is essentially a small, muscular pump that is trusty for propelling deoxygenated blood to the lungs, while correspondingly pumping nutrient rich, oxygenated blood to the clay. at once the blood leaves the left ventricle, it enters the aorta and corresponding earnings of arteries that constitute the circulatory system. contrast vass are divided into four categories arteries (take oxygenated blood away from the heart to the body), arterioles (branch discover from the arteries principal into the capillaries), capillaries (smallest of blood vessels where gas and nutrient exchange choke s), and veins (carry deoxygenated blood from the body to the heart). Arteries and veins have different functions however, they both are composed of three diaphanous horizontal surfaces tunica intima, tunica media, and the tunica adventita 2. The tunica intima is the innermost socio-economic class of some(prenominal) given blood vessel it embarrasss the endothelial ocean liner and a socio-economic class of connective tissue containing variable amounts of elastic fibers 3. The tunica media is the middle layer which contains concentric sheets of good-tempered pass composed of elastin and collagen fibers 3. It is this smooth muscle that when turned on(p) by the sympathetic nervous system either constricts, decreasing the diam of the lumen (vasoconstriction), or it relaxes, increasing the diameter of the vessel lumen (vasodilation) 2 the fictional character of these vasoactivators pass on be discussed later in this paper. Lastly, the tunica adventitia is the out most layer , which is composed of collagen and elastin fibers. Often, this outer(a) layer is blended into adjacent tissues allowing the anchoring and stabilization of some vessels 2.As the heart is an organ continuously doing work, the cardiac muscle electric cells are in need of a constant supply of oxygen and nutrients. It is the coronary circulation that is amenable for the blood supply to the cardiac tissues, via an extensive network of coronary arteries. Both the left and right coronary arteries originate from the mean of the ascending aorta at heart the aortic sinus 1,3. The autonomic nervous system (ANS) plays an important fiber as neurogenic stimuli have the tycoon to view as the finale of coronary vasodilation. This neuromodulation governs the rate of breathing out of vasoconstrictive norepinephrine (NE), which is amplification by the adrenergic activation and angiotension II (AII) 1. Other vasoconstrictors include 1 and 2 adrenergic bodily function, AII, and endothelin. Va soconstrictive stimuli are also responsible for an adjoin in detached cytosolic calcium in the vascular smooth muscle, go awaying in the homeostasis of myocardial contraction 4. centrally, these vasoconstrictive adrenergic influences are opposed by vasodilatory influences such(prenominal) as -adrenergic vascular receptors and metabolic mechanisms such as nitric oxide (NO), adenosine (ATP) and the activation of vascular ATP dependent potassium channels (KATP) 1. With this, at that place are three essential regulators of coronary tone i) the metabolic vasodilatory system ii) the neurogenic control system ( much than(prenominal) vasoconstrictive than vasodilatory) and iii) the vascular epithelium, which great deal be either vasodilatory by releasing NO or vasoconstrictive by releasing endothelin-1 1, 4. Thus, we must watch in mind that endothelin-1 is one of the to a greater extent powerful vasoconstrictors, especially when endothelial damage is extensive 1, 4. These vasoact ive substances are mad by their respective and very different, signaling pathways gum olibanum add to the complexities of atherosclerosis, devising it a true multi federal agential illness.As with former(a)(a) vessels within the body, when in that respect is an enlarged demand for oxygen, vasodilation of the coronary arteries egests. This vasodilation is normally mediated by the deplete of NO from healthy endothelium in contrast, when the endothelium is damaged, it releases vasoconstrictive endothelin 1. It is be gain of their vital importance that the coronary arteries have gained popular attention when they are partially or all told occluded by atherosclerotic memorial tablets. These atherosclerotic plaques cause inadequate oxygen supply to the cardiac tissue resulting in tissue death (myocardial infarct), and sundry(a) other fashions of heart diseases 1. Therefore without an adequate supply of oxygen and nutrients to the myocardial muscle, the heart allow cease t o function properly.This basic free-baseation will give us a better idea on how a healthy cardiovascular system functions. Therefore allowing us to understand the forceful effects a disease such as atherosclerosis privy have on this system. The important focus of this paper will be on atherosclerosis however other forms of heart disease will be discussed to solidify the idea of how destructive atherosclerosis tush be. Thus, the relaxation of this paper will focus on the cellular mechanisms behind atherosclerosis, along with old and new thoughts in regards to the etiology and preaching options for this type of heart disease.Their Underlying Relation of Atherosclerosis to Other Coronary Heart DiseasesCardiovascular disease (CVD) has emerged as the dominant chronic disease in legion(predicate) parts of the world, and early in the 21st century it is predicted to become the main cause of dis readiness and death worldwide 5. CVD represents a very liberal category of conditions th at affect the heart and circulatory system. Common risk factors include blood wedge (hypertension), total cholesterol ( low-density lipoprotein and HDL), diabetes, obesity, left ventricular hypertrophy, and heritable predisposition 6. The most prominent and worrisome of these diseases are those that contribute to coronary heart disease. The coronary heart diseases of interest include ischaemic heart disease, angina pectoris pectoris, myocardial infarct, and most importantly, atherosclerosis. As a result of these coronary heart diseases, cardiac output is practically depressed and oftentimes increases the oxygen demand needed by the cardiac tissues. Therefore the effects of coronary heart disease cannot be taken lightly, as the effects can be senior highly variable, ranging from diffuse damage, to localized narrowing or stricture of the coronary arteries 7. Importantly, these coronary diseases have direct vasodilatory effects of the coronary circulation, playacting by the ad ministration of adenosine and NO, and the opening of the KATP channels also the vascular endothelium is damaged, ca apply the vasodilatory stimuli to be overcome by the vasoconstrictors such as endothelin and AII 1. By discussing these other forms of coronary heart disease, the reader will better understand the relationship between these diseases and atherosclerosis allowing a better understanding of the importance for go onion and treatment strategies of coronary heart disease.Traditionally, it has been thought that the major cause of myocardial ischemia is the result of fixed vessel narrowing and freakish vascular tone, caused by atherosclerosis- bring on endothelial cell dysfunction 6. This narrowing of the coronary arteries reduces the blood and oxygen geological period to the myocardial tissues. It is the cessation of the myocardial blood shine out-of-pocket to atherosclerotic occlusions that results in the immediate physiological and metabolic changes. Unfortunately, th e heart cannot increase oxygen extraction on demand, therefore any supernumerary oxygen requirements are met by increasing the blood flow and autoregulation of the coronary vasculature 6. This oxygen imbalance whitethorn also be an underlying cause for not only myocardial ischemia, but contractile cardiac dysfunction, arrhythmias, infarction, and sometimes death 5. However, important to note is the hearts unique ability to adapt to these sudden changes in coronary blood flow by correspondingly decreasing the rate of cardiac contraction 1,5. Thus, the diminish work during ischemia proportionately decreases the oxygen demand and helps conserve the underperfused myocardium 1 this cherishive mechanism prevents further damage and cell death collectable to decreased oxygen levels.Besides physiological factors, there are also metabolic changes that occur immediately after the sign onset of ischemia. The myocardial zipper transfiguration shifts from aerobic (mitochondrial) metabolism to anaerobic glycolysis within a few seconds 5 simultaneously, the energy depletion causes the myocardial contraction to diminish, eventually ceasing altogether. Consequently, due to the inhibited mitochondrial metabolism, there is an increase in adenosine concentrations which causes the adenosine to bind to the smooth muscle receptors, decreasing calcium gate into the cells, thus causing relaxation due to vasodilation 7,8. Overall, the inability to meet the myocardial oxygen demand often results in severe, vice-like chest bother, or more unremarkably know as angina pectoris.Angina pectoris often is an associated omen of myocardial ischemia and is the normal medical term used to come upon chest pain or discomfort due to coronary heart disease without myocardial necrosis. Interestingly, angina can also occur in people with valvular disease, hypertrophic cardiomyopathy, and uncontrolled high blood pressure (hypertension). soon there are three major variations of angina pectoris . The first is known as changeless angina, or more commonly, chronic stable angina. This form of angina is characterized by a fixed, obstructive atheromous plaque in one or more coronary arteries 1,7,9. Patients who suffer from chronic stable angina usually have episodes of discomfort that are usually predictable. The discomfort is see shortly after over exertion and/or mental or emotional stress these symptoms are usually relieved by rest, nitroglycerin, or a combination of both. Again, the major contributing factor in stable angina is due to the coronary vasoconstriction caused by atherosclerotic endothelial dysfunction 7.A second form of angina is known as mobile angina. Unstable angina is characterized by unexpected chest pain which usually occurs at rest without any type of physical exertion. This chest pain is due to coronary artery stricture caused by atherosclerotic plaque or the narrowing of the vessels obstructed by blood clots. Also other key factors in unstable angin a include lighting and contagion 7,9. The last form of angina is the variant angina, or more commonly known as Prinzmetals Angina 7. This form of angina is manifested by episodes of focal coronary artery spasm in the absence of atherosclerotic lesions 7,9. The coronary vasospasm alone reduces coronary oxygen supply and is thought to be caused in rejoinder to abnormal endothelial dependent vasodilators (Acetylcholine ACh, and serotonin) 1,7. These coronary spasms are often manifested by the coronary atheroma which damages the vascular endothelium, causing a decreased intersection of vasodilators (NO and prostaglandin PGI2) and an increase in vasoconstrictive factors such as endothelin and AII 1. Often when someone is diagnosed with either form of angina, they are usually monitored closely, as they are at an increased risk of a heart contend (myocardial infarction), cardiac arrest, or sudden cardiac death.A myocardial infarction (heart attack) is the resultant complication when the blood supply to part of the heart is interrupted. This ischemic oxygen shortage causes damage and sometimes death to the heart tissues. Important associated risk factors include atherosclerosis, previous heart attack or stroke, smoking, high LDL and low HDL cholesterol levels, diabetes, obesity, and high blood pressure 10. Often referred to as an smashing myocardial infarction, it is part of the acute coronary syndromes which includes ST segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina 1,7,10.As with angina, the pain experienced may result from the release of mediators such as adenosine and lactate from the ischemic myocardial cells onto the local nerve endings 7. This ischemic persistence triggers a process called the ischemic cascade 5, which usually results in tissue death due to necrosis. legitimate factors such as psychological stressors and physical exertion have been determine as major trigg ering factors involved with acute myocardial infarctions. Often these acute myocardial infarctions are brought on by the rupturing of atherosclerotic plaques, which then come along thrombus (blood clot) formation causing further occlusion of the arteries. This atherosclerotic blockage thus initiates myocardial necrosis, which in turn activates systemic responses to inflammation causing the release of cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF) 7,10. Damaged caused by myocardial necrosis includes i) wrong of critical amount of ATP, ii) membrane damage induced metabolically or mechanically, iii) formation of free radicals, iv) calcium overload, and v) sodium pump inhibition 1.Apart from damaging the myocardial tissue, an acute myocardial infarction can cause varying pathophysiological changes in other organ systems. whatever of these changes include decreased pulmonary function gas exchange, ventilation, and distribution of perfusion, decreased vital capac ity reducing in hemoglobins simile for oxygen, causes hyperglycemia and damage glucose function, increases the plasma and urinary catecholamine levels (thus enhancing thrombocyte aggregation), and also has been found to increase blood viscosity 5. From the above evidence, we can see that coronary heart disease should not be looked at light heartedly. It is due to their similarity that the different coronary heart diseases can be diagnosed using a given set of molecular markers and other diagnostic tools.serum cardiac markers have become astray used when it comes to diagnosis the extent and type of coronary heart disease a patient is symptomatic of. Also, these tests have allowed physicians to diagnose an additional one third of patients that do not exhibit all criteria of a given disease 5, thus preventing more premature deaths. The most common of these cardiac markers are myocardial snarf creatine kinase (CK-MB), and cardiac troponin l and t (cTnl and cTnT). These markers ar e often found within a blood sample as levels start to rise between 3-8 hours and 3-4 hours respectively 7. More recently, new risk factor biomarkers such as C-reactive protein (CRP), myeloperoxidase (MPO) 11, 12, and lipoprotein-associated phospholipase A2 12 are being studied more in think as alternative cardiac markers. Although cardiac biomarkers are heavily used, the utilisation of noninvasive technologies also plays a major role in diagnosing coronary heart disease. These noninvasive methods include electrocardiography, exercise stress testing, echocardiography, cardiovascular MRI, and CT imaging of the heart 5. Some invasive, intravascular techniques include ultrasound, thermography, near infrared frequency spectroscopy, cardiac catheterization, and cardiac angiography 12.As coronary heart disease is the tiping cause of hospitalization and death among todays population, native and utility(prenominal) prevention strategies need to be considered with the utmost importanc e. Primary prevention slackly substance the effort set forth to modify risk factors and prevent their development delaying or preventing new onset coronary heart disease 13. As for secondary prevention, this often refers to the therapy involved to reduce recurrent coronary heart disease events thus secondary preventions are essentially treatment strategies. The most common and less intensive of these treatment strategies are that of the pharmaceutic therapies. Often, these medicine regimes range from the daily aspirin intake to angiotension-converting enzyme inhibitors (ACEi), to -blockers and nitrates 12. These drug therapies often lower the risk of recurrent cardiovascular events. Unfortunately daily drug regimes do not work for everyone. Some people have their coronary heart disease surgically corrected either by angioplasty (insertion of stent to keep the blocked vessel open) or by means of a more complex surgery consisting of a single to threefold coronary artery bypass. Wi th everything considered, drug therapies and surgical correction are only a means of correcting the problem patients are also encouraged to increase physical activity and change their daily dietary habits in becoming more flourishing in reducing risk of development or growth of coronary artery disease.These different forms of coronary heart disease are very closely related to one another(prenominal), more importantly, closely related to atherosclerosis. As discussed previously, coronary heart diseases are characterized by the narrowing or stenosis of the coronary vessels, usually caused by the atherosclerotic plaque formation due to endothelial cell dysfunction. As a result, atherosclerosis is the underlying mechanism for ischemic heart disease, angina pectoris (stable, unstable, and variant), myocardial infarction and sudden cardiac death 12. Therefore it is important to understand the cellular pathogenesis of atherosclerosis, which will tinge to a better understanding resultin g in better prevention and treatment strategies for all forms of atheroma induced coronary heart disease.Introduction to AtherosclerosisAtherosclerosis, the primary quill etiology of cardiovascular disease, is characterized by intimal plaque that forms as a time-dependent response to arterial injury 14. Atherosclerosis is a disease alter the arterial blood vessels, which is commonly known as hardening of the arteries. This form of coronary heart disease is the principle informant of both cerebral and myocardial infarction, gangrene of the extremities, and loss of function of both organs and tissues 15 this disease is ultimately responsible for a majority of deaths in North America, Europe, and lacquer 16. The method of atherogenesis is not fully understood, however there are a number of current models that suggest that stressors corrupt the vascular integrity allowing the abnormal accumulation of lipides, cells and extracellular matrix within the arterial wall 7. collect to it s very slow progression, it is not surprising that atherosclerosis goes undetected and remains asymptomatic until the atheroma obstructs the blood flow within the artery 14,16 hence atherosclerosis is often referred to as the silent killer.Often, the atherosclerotic plaque can be divided into three distinct components. The first being the atheroma, which is the nodular accumulation of the soft, flaky, and yellow material of the plaques, usually composed of macrophages closest to the lumen of the artery. The second component is the underlying areas of cholesterol crystals, and the third is the calcification at the outer base of the older/more advanced lesions 17. Collectively, these components constitute the basis of the atherosclerotic plaques. These atherosclerotic plaques are responsible for the arterial narrowing (stenosis) or they may rupture and provoke thrombosis 7, 14, 15 either way the atherosclerotic plaque causes an meager blood supply to the heart and other organs. As discussed previously, the atherosclerotic plaques lead to other major complications such as ischemia, angina pectoris, myocardial infarction, stroke, and causes stricken blood flow to the kidneys and lower extremities. Interestingly, arteries without many branches (internal mammary or stellate arteries) tend not to develop atherosclerosis 5.One of the most evidence-based hypotheses regarding atherogenesis is that of the response-to-injury venture. This hypothesis suggests that the atherosclerotic lesions represent a specialized form of a protective, inflammatory, fibroproliferative response to variant forms of insult to the arterial wall 15. This seems to be a reoccurring theme, as now atherosclerosis is considered to be a form of chronic inflammation between change lipoproteins, monocyte derived macrophages, T cells, and normal cellular elements of the arterial wall 16, 18. As with other diseases, there are a number of physiological factors that increases ones risk for develop ing atherosclerosis. These factors include age, sex, diabetes or impaired glucose tolerance, hypertension, tobacco smoking, estrogen status, physical inactivity, metabolic syndrome, and dyslipidemia 7, 19.The remainder of this paper will shift its focus to the pathogenesis of atherosclerosis including the ideas of endothelial dysfunction, lipoprotein introduction and modification, enlisting of leukocytes, recruitment of smooth muscle as well as other contributing factors such as dyslipidemia, hypertension, and diabetes. Also, the cellular complications of atherosclerosis will be discussed.endothelial Dysfunction Primary Initiation of AtherosclerosisHealthy arteries are often responsive to unlike stimuli, including the shear stress of blood flow and various neurogenic signals. These endothelial cells secrete substances that modulate contraction and dilation of the smooth muscle cells of the underlying medial layer 7. These healthy endothelial cells are also responsible for the in hibition of migration of smooth muscle cells to the intimal layer 20 and they also play an important role in immune responses. mean(prenominal) functional characteristics of healthy endothelium includes i) ability to act as a semipermeable barrier between the intravascular and tissue topographic point, ii) ability to modify and transport lipoproteins into the vessel wall, iii) acts as a non-thrombogenic and non-leukocyte adherent surface, iv) acting as a source of vasoactive molecules, v) act as a source of growth regulatory molecules, and vi) a source of connective tissue matrix molecules 14, 15. Overall, in a normal, healthy state, the endothelial layer provides a protective, non-thrombogenic surface with homeostatic vasodilatory and anti-inflammatory properties 7.It is widely known that the endothelium is responsible for the synthesis and release of several vasodilators such as NO, endothelium derived hyperpolarizing factors (EDHFs), endothelial derived relaxing factors (EDRFs ), and prostacyclin (PGI2) 7, 20. These vasodilators utilise a G-coupled signaling pathway, where NO diffuses from the endothelium to the vascular smooth muscle where it activates guanylyl cyclase (G-cyclase) 7. The G-cyclase in turn forms cyclic guanosine monophosphate (cGMP) from cGTP an increase in cGMP results in smooth muscle relaxation which subsequently involves a reduction of cytosolic Ca2+. Aside from these anti-thrombic substances, the endothelium also produces prothrombic molecules including endothelin-1 and other endothelium derived contracting factors (EDFCs) 20. Importantly, the endothelium derived NO not only modulates the tone of the underlying vascular smooth muscle, but is also responsible for the inhibition of several proatherogenic processes. These processes include smooth muscle proliferation and recruitment, platelet aggregation, oxidation of low niggardliness lipoproteins (LDLs), monocyte and leukocyte recruitment, platelet love, and the synthesis of inflam matory cytokines 20. Therefore, relating back end to the response-to-injury hypothesis, loss of these endothelial functions promotes endothelial dysfunction, thus acting as the primary event in atherogenesis.Endothelial dysfunction is considered to be an initiating event which leads to the pathogenesis of atherosclerosis. For this reason endothelial dysfunction has been shown to be of prognostic significance in predicting such vascular events as heart attacks or strokes 21. It has been established that endothelial cell dysfunction is characterized by alterations in vascular permeability and inadequate production of NO 4, 22, 23 thus predisposing the endothelium to the development of atheromas. Interestingly, in response to initial atheroma formation, the arteries often dilate, causing outward remodeling of the vessel for this accommodation 4 however if this remodeling is insufficient, the blood flow is impaired, thus causing ischemia 4. Several physical and chemical factors are res ponsible for affecting normal endothelial function. Some common factors discussed previously include diabetes, hypertension, hypercholesterolemia, smoking, age, diet, and physical inactivity. However, more importantly are the physiological factors i) disability of the permeable barrier, ii) release of inflammatory cytokines, iii) increase transcription of cell-surface adhesion molecules, iv) adapted release of vasoactive substances (PGI2 and NO), and v) interference with normal anti-thrombotic properties 7.Commonly, endothelial dysfunction is characterized by the reduction of vasodilators NO and PGI2, and the increase of various endothelial derived contracting factors 23, 24. This impairment may also predispose the vessels to vasospasm 22. This decrease in NO bioavailability is thought to cause a decreased level of expression of endothelial cell NO synthetase (eNOS) 21, thus reducing the likelihood of vasodilation from occurring. Apart from its vasodilatory role, NO is also respons ible for resisting inflammatory activation of endothelial functions such as expression of the adhesion molecule VCAM-1 5. NO has also appeared to exert anti-inflammatory action at the level of gene expression by interfering with nuclear factor kappa B (NFB), which is important in regulating numerous genes involved in inflammatory responses 5 these inflammatory responses will be discussed later on. The other common vasodilator, PGI2 is also reduced during endothelial dysfunction. PGI2 is a major product of vascular cyclooxygenase (COX) and is considered a potent inhibitor of platelet aggregation 20. Like NO, PGI2 is an endothelial derived product which is often produced in response to shear stress (commonly caused by blood flow) and hypoxia 20. By understanding the other roles NO and PGI2 play within the endothelium, we can see that a decrease in one or the other ultimately leads to dysfunction and disruption of the endothelium. As a result of vasodilator reduction, the endothelium o ften synthesizes and releases EDCFs causing endothelial constriction. The major constrictors include superoxide anion anions (which act by scavenging NO thus further reducing NO levels), thromboxane A2, endothelin-1, AII, and -adrenergic factors 20. Unlike the vasodilators, the vasoconstrictors utilize two signaling pathways. The 1-adrenergic receptor signaling pathways utilize the same G-coupled pathway as the vasodilators (discussed previously) however instead of cGMP it utilizes cyclic adenosine monophosphate (cAMP) 1. The other constrictors including thromboxane A2, endothelin-1 and AII utilize the cAMP-dependent protein kinase pathway where the activated kinase acts as a trigger for various physiological effects, including increased contractile activity on the arterioles 1.The overall progression of atherosclerotic plaque formation is best illustrated in Figure 1, which showcases multiple events that are simultaneously triggered by endothelial dysfunction.Apart from the imbal ance of vasoactivators, endothelial dysfunction is responsible for initiating two other separate pathways that also enter in the progression of plaque formation and growth. Lipoprotein entry is the next initial stage in atherogenesis. This is then followed by the modification and entry of lipoproteins, the recruitment of leukocytes, and the migration and proliferation of smooth muscle cells. Overall this evolutionary process best represents the formation of atherosclerotic plaques within the vessels.Lipoprotein Entry and ModificationLipid accumulation is another major manifestation of the vascular response to injury, and is accelerated by the entry and modification of lipoproteins. Lipoproteins are composed of both lipids and proteins, and help transport piss-insoluble fats passim the bloodstream 7, 25. The lipid core is surrounded by hydrophilic phospholipids, free cholesterol and apoliporoteins where the protein portion has a charged group, aimed outwards to attack water molecu les, thus making the lipoproteins soluble in the plasma of the blood 26, 27. In total, there are five major classes of lipoproteins the chylomicrons, very low constriction lipoproteins (VLDLs), intermediate low density lipoproteins (ILDLs), low density lipoproteins (LDLs), and the high density lipoproteins (HDLs). The chylomicrons provide the primary means of transport of dietary lipids, while the VLDLs, ILDLs, LDLs, and HDLs function to transport endogenous lipids 16, 25. Of the lipoproteins, the LDLs are of most interest. Interestingly high LDL levels often correlate closely with atherosclerosis development, whereas high HDL levels protect against atherosclerosis the HDL protection is thought to be related to its ability to transport lipids away from the peripheral tissues back to the liver for disposal 7.A key component to the accumulation of lipids is due to the endothelial dysfunction, which causes a loss of selective permeability and barrier function. This ineffective permeab ility allows for the entry of LDLs into the intima lining of the vessels 7, 16. The highly elevated circulating levels of LDLs are colloquially referred to as having hyperlipidemia, hypercholesterolemia, or dyslipidemia 7, 25-27. In either case, once the LDL has entered the intima of the vessel, the LDL starts accumulating in the subendothelial space by binding to components of the extracellular matrix, the proteoglycans lipolytic and lysosomal enzymes also play a role in lipid accumulation 27. Importantly, statins lower circulating cholesterol levels by indirectly inhibiting HMG CoA-reductase (rate limiting enzyme required for endogenous cholesterol biosynthesis 16. This results in the decrease of intracellular cholesterol levels, which leads to the activation of SREBP, upregulation of LDL receptors, and the clearance from plasma degradation of LDL thus reducing circulating LDL levels 16.When the lipid accumulation increases the residence time that the LDL occupies within the vesse l wall, it allows more time for lipoprotein modification 7 which appears to play a key role in the continued progression of the atherosclerotic plaque. Often, endothelial cell dysfunction leads to the modify expression of lipoprotein receptors used to internalize and modify various lipoproteins 14. These changes usually occur via oxidative modifications. The oxidative modification hypothesis (figure 2) focuses on the concept that LDLs in their native state are often not atherogenic 27. It is believed, however, that LDLs are modified chemically by the endothelial cells 26 and are readily internalized by macrophages (formation of the fizz cell) via the scavenger-receptor pathway 27. Essentially the trapped LDL within the subendothelial space is change by the resident vascular smooth muscle cells, endothelial cells, and macrophages. As a result t