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Pathogenic Etiology of Atherosclerosis

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Published: Mon, 05 Feb 2018

Atherosclerosis Heart Coronary

Special Topics in Pathophysiology

Introduction to the Components of the Cardiovascular System:

To understand the basis of this paper, the pathophysiology of atherosclerosis, it is vital to appreciate the basic physiology of the heart, circulatory system, and most importantly, the coronary arteries. This fundamental comprehension will lay the foundation to better understand the devastation caused to the coronary arteries by the pathogenesis of atherosclerosis. This may also provide insight into prevention and treatment strategies to counteract the destructive mechanism of this disease.

The heart is a very small, vitally important organ composed of four muscular chambers: the right and left atria, and the right and left ventricles. The atria have relatively thin muscular walls, allowing them to be highly distensible [1]; whereas the ventricles are of greater muscular thickness, which is vital for pumping the blood to the pulmonary and systemic circuits. A normal healthy heart has two main functions: to pump blood to the pulmonary circuit where the blood becomes oxygenated and to pump the oxygen-rich blood to the systemic circuit. The heart is essentially a small, muscular pump that is responsible for propelling deoxygenated blood to the lungs, while correspondingly pumping nutrient rich, oxygenated blood to the body. Once the blood leaves the left ventricle, it enters the aorta and corresponding network of arteries that constitute the circulatory system.

Blood vessels are divided into four categories: arteries (take oxygenated blood away from the heart to the body), arterioles (branch out from the arteries leading into the capillaries), capillaries (smallest of blood vessels where gas and nutrient exchange occurs), and veins (carry deoxygenated blood from the body to the heart). Arteries and veins have different functions; however, they both are composed of three distinct layers: tunica intima, tunica media, and the tunica adventita [2]. The tunica intima is the innermost layer of any given blood vessel; it includes the endothelial lining and a layer of connective tissue containing variable amounts of elastic fibers [3]. The tunica media is the middle layer which contains concentric sheets of smooth muscle composed of elastin and collagen fibers [3]. It is this smooth muscle that when stimulated by the sympathetic nervous system either constricts, decreasing the diameter of the lumen (vasoconstriction), or it relaxes, increasing the diameter of the vessel lumen (vasodilation) [2]; the role of these vasoactivators will be discussed later in this paper. Lastly, the tunica adventitia is the outer most layer, which is composed of collagen and elastin fibers. Often, this outer 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 cells are in need of a constant supply of oxygen and nutrients. It is the coronary circulation that is responsible 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 base of the ascending aorta within the aortic sinus [1,3]. The autonomic nervous system (ANS) plays an important role as neurogenic stimuli have the ability to restrain the extent of coronary vasodilation. This neuromodulation governs the rate of release of vasoconstrictive norepinephrine (NE), which is increased by the adrenergic activation and angiotension II (AII) [1]. Other vasoconstrictors include α1 and α2 adrenergic activity, AII, and endothelin. Vasoconstrictive stimuli are also responsible for an increase in free cytosolic calcium in the vascular smooth muscle, resulting in the homeostasis of myocardial contraction [4].

Importantly, these vasoconstrictive adrenergic influences are opposed by vasodilatory influences such as β-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, there are three essential regulators of coronary tone: i) the metabolic vasodilatory system; ii) the neurogenic control system (more vasoconstrictive than vasodilatory); and iii) the vascular epithelium, which can be either vasodilatory by releasing NO or vasoconstrictive by releasing endothelin-1 [1, 4]. Thus, we must keep in mind that endothelin-1 is one of the more powerful vasoconstrictors, especially when endothelial damage is extensive [1, 4]. These vasoactive substances are activated by their respective and very different, signaling pathways; thus contributing to the complexities of atherosclerosis, making it a true multifactorial disease.

As with other vessels within the body, when there is an increased demand for oxygen, vasodilation of the coronary arteries occurs. This vasodilation is usually mediated by the release of NO from healthy endothelium; in contrast, when the endothelium is damaged, it releases vasoconstrictive endothelin [1]. It is because of their vital importance that the coronary arteries have gained popular attention when they are partially or completely occluded by atherosclerotic plaques. These atherosclerotic plaques cause inadequate oxygen supply to the cardiac tissue resulting in tissue death (myocardial infarction), and various other forms of heart diseases [1]. Therefore without an adequate supply of oxygen and nutrients to the myocardial muscle, the heart will cease to function properly.

This basic foundation will give us a better idea on how a healthy cardiovascular system functions. Therefore allowing us to understand the drastic effects a disease such as atherosclerosis can have on this system. The main 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 can be. Thus, the remainder of this paper will focus on the cellular mechanisms behind atherosclerosis, along with old and new thoughts in regards to the etiology and treatment options for this type of heart disease.

Their Underlying Relation of Atherosclerosis to Other Coronary Heart Diseases:

Cardiovascular disease (CVD) has emerged as the dominant chronic disease in many parts of the world, and early in the 21st century it is predicted to become the main cause of disability and death worldwide [5]. CVD represents a very broad category of conditions that affect the heart and circulatory system. Common risk factors include: blood pressure (hypertension), total cholesterol (LDL and HDL), diabetes, obesity, left ventricular hypertrophy, and genetic 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: ischemic heart disease, angina pectoris, myocardial infarction, and most importantly, atherosclerosis. As a result of these coronary heart diseases, cardiac output is often depressed and often 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 highly variable, ranging from diffuse damage, to localized narrowing or stenosis of the coronary arteries [7]. Importantly, these coronary diseases have direct vasodilatory effects of the coronary circulation, acting by the formation of adenosine and NO, and the opening of the KATP channels; also the vascular endothelium is damaged, causing 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 prevention 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 abnormal vascular tone, caused by atherosclerosis-induced endothelial cell dysfunction [6]. This narrowing of the coronary arteries reduces the blood and oxygen flow to the myocardial tissues. It is the cessation of the myocardial blood flow due to atherosclerotic occlusions that results in the immediate physiological and metabolic changes. Unfortunately, the heart cannot increase oxygen extraction on demand, therefore any additional oxygen requirements are met by increasing the blood flow and autoregulation of the coronary vasculature [6]. This oxygen imbalance may 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 heart’s unique ability to adapt to these sudden changes in coronary blood flow by correspondingly decreasing the rate of cardiac contraction [1,5]. Thus, the decreased work during ischemia proportionately decreases the oxygen demand and helps conserve the underperfused myocardium [1]; this protective mechanism prevents further damage and cell death due to decreased oxygen levels.

Besides physiological factors, there are also metabolic changes that occur immediately after the initial onset of ischemia. The myocardial energy metabolism 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 entry 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 pain, or more commonly known as angina pectoris.

Angina pectoris often is an associated symptom of myocardial ischemia and is the common medical term used to describe 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). Currently there are three major variations of angina pectoris. The first is known as stable 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 experienced 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 unstable 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 stenosis caused by atherosclerotic plaque or the narrowing of the vessels obstructed by blood clots. Also other key factors in unstable angina include inflammation and infection [7,9]. The last form of angina is the variant angina, or more commonly known as Prinzmetal’s 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 response 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 production 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 attack (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 acute 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. Certain factors such as psychological stressors and physical exertion have been identified as major triggering factors involved with acute myocardial infarctions. Often these acute myocardial infarctions are brought on by the rupturing of atherosclerotic plaques, which then promote 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 (TNFα) [7,10]. Damaged caused by myocardial necrosis includes: i) loss 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. Some of these changes include: decreased pulmonary function – gas exchange, ventilation, and distribution of perfusion, decreased vital capacity; reduction in hemoglobin’s affinity for oxygen, causes hyperglycemia and impaired glucose function, increases the plasma and urinary catecholamine levels (thus enhancing platelet 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 widely used when it comes to diagnosing 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 bound creatine kinase (CK-MB), and cardiac troponin l and t (cTnl and cTnT). These markers are 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 depth as alternative cardiac markers. Although cardiac biomarkers are heavily used, the role 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 spectroscopy, cardiac catheterization, and cardiac angiography [12].

As coronary heart disease is the leading cause of hospitalization and death among today’s population, primary and secondary prevention strategies need to be considered with the utmost importance. Primary prevention generally means 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 pharmaceutical therapies. Often, these drug regimes range from the daily aspirin intake to angiotension-converting enzyme inhibitors (ACEi), to β-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 multiple coronary artery bypass. With 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 successful in reducing risk of development or progression of coronary artery disease.

These different forms of coronary heart disease are very closely related to one another, 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 lead to a better understanding resulting in better prevention and treatment strategies for all forms of atheroma induced coronary heart disease.

Introduction to Atherosclerosis:

Atherosclerosis, the primary etiology of cardiovascular disease, is characterized by intimal plaque that forms as a time-dependent response to arterial injury [14]. Atherosclerosis is a disease affecting the arterial blood vessels, which is commonly known as “hardening of the arteries.” This form of coronary heart disease is the principle source 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 Japan [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 lipids, cells and extracellular matrix within the arterial wall [7]. Due to its 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 insufficient 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 impaired blood flow to the kidneys and lower extremities. Interestingly, arteries without many branches (internal mammary or radial arteries) tend not to develop atherosclerosis [5].

One of the most evidence-based hypotheses regarding atherogenesis is that of the response-to-injury hypothesis. This hypothesis suggests that the atherosclerotic lesions represent a specialized form of a protective, inflammatory, fibroproliferative response to various 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 modified 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 one’s risk for developing 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 entry and modification, recruitment 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 Atherosclerosis:

Healthy arteries are often responsive to various 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 inhibition of migration of smooth muscle cells to the intimal layer [20] and they also play an important role in immune responses. Normal functional characteristics of healthy endothelium includes: i) ability to act as a permeable barrier between the intravascular and tissue space, 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 utilize 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 density lipoproteins (LDLs), monocyte and leukocyte recruitment, platelet adhesion, and the synthesis of inflammatory cytokines [20]. Therefore, relating back 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 responsible 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) impairment of the permeable barrier, ii) release of inflammatory cytokines, iii) increase transcription of cell-surface adhesion molecules, iv) altered 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 responsible 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 (NFκB), 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 often synthesizes and releases EDCFs causing endothelial constriction. The major constrictors include superoxide anions (which act by scavenging NO – thus further reducing NO levels), thromboxane A2, endothelin-1, AII, and α-adrenergic factors [20]. Unlike the vasodilators, the vasoconstrictors utilize two signaling pathways. The α 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 imbalance of vasoactivators, endothelial dysfunction is responsible for initiating two other separate pathways that also participate 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 Modification:

Lipid 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 water-insoluble fats throughout 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 molecules, 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 density 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 permeability 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 vessel 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 altered 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 foam cell) via the ‘scavenger-receptor’ pathway [27]. Essentially the “trapped” LDL within the subendothelial space is oxidized by the resident vascular smooth muscle cells, endothelial cells, and macrophages. As a result t


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