Pathogenic Etiology of Atherosclerosis

Pathogenic Etiology of Atherosclerosis 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 ÃŽ ±1 and ÃŽ ±2 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 ÃŽ ²-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 vasoconstrict ion 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 (TNFÃŽ ±) [7,10]. Damaged caused by myocardial necrosis includes: i) loss of critical amount of ATP, ii) membrane damag e 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 metho ds 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 ÃŽ ²-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 dise ase 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 â€Å"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 obstr ucts the blood flow within the artery [14,16]; hence atherosclerosis is often referred to as the â€Å"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 prote ctive, 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 (NFÃŽ ºB), 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 ÃŽ ±-adrenergic factors [20]. Unlike the vasodilators, the vasoconstrictors utilize two signaling pathways. The ÃŽ ± 1-adrenergic receptor signaling pathways utilize the same G-coupled pathway as the vasodilators (discussed previously) however instead of cGMP; it ut ilizes 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 â€Å"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. Inter estingly 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 â€Å"trapped† LDL within the subendothelial space is oxidized by the resident vascular smooth muscle cells, endothelial cells, and macrophages. As a result t

Mythological Women Essay

Attitudes toward women in mythology reflect the attitudes that still exist today around the world. In mythology women always seem to mess up and make mistakes. Women are viewed as incapable in mythology. The attitudes toward women in both Judeo-Christian/Western and Greek mythology are negative. One of the three types of mythology that are going to be discussed about is humanity mythology. In Judeo-Christian/Western humanity mythology, there is the parable of â€Å"Adam and Eve†. In â€Å"Adam and Eve†, God tells them to not eat from the forbidden tree. Eve, the woman, is tempted and ends up disobeying God by eating an apple from the tree that was forbidden. On the other hand, in Greek humanity mythology there is the story of Pandora. Pandora was given a box and was told to never open the box. Curiosity got the best of Pandora and she ended up disobeying by opening the box. In humanity mythology women are portrayed as not being able to follow instructions and obey. The next type of mythology is the animal/plant mythology. In Judeo-Christian/Western animal/plant mythology, you have the parable of â€Å"Adam and Eve† again. In the parable, Adam the man, is given the responsibility to name the animals. While in Greek animal/plant mythology, you have the myth of how spiders came to be. There was a Goddess named Athena who challenged Arachne at weaving. Arachne was the best weaver there. After loosing, Athena turned Arachne into a spider so she would weave webs forever. In animal/plant mythology, women are viewed as incapable to complete tasks and also viewed as jealous. The last type of mythology is hero mythology. In Judeo-Christian/Western hero mythology, you have superhero and trickster schemes. Without a trickster there is no superhero to solve the problem. In the superhero community, almost every superhero is male. On the other hand, in Greek hero mythology you have The Odyssey. In The Odyssey, you have Odysseus who is away for twenty â€Å"long† years. Odysseus’s wife has been mourning for his arrival and has remained clean and faithful. In the meantime, Odysseus is sleeping with other women. Hero mythology portrays the dominance of men and their image of strength. Hero mythology also portrays the double standard of  what men expect for women. In conclusion, bad attitudes toward women that are seen in Judeo-Christian/Western and Greek mythology still exist today. In humanity mythology, women are portrayed as incapable of obeying and following instructions. In animal/plant mythology, women are viewed as incapable to complete tasks and also very jealous. In hero mythology, men are seen as the ones with dominance, strength, and superiority and you can see a double standard in the expectations of morality. The attitudes toward women in both Judeo-Christian/Western and Greek mythology are negative.

System Forensics

System forensics is the process of systematically examining computer media as well as network components, software, and memory for evidence. System forensics involves collecting, preserving, analyzing, and documenting evidence to reconstruct user actively. Appropriately collected evidence Is often presented In court to solve criminal cases and prosecute criminals. 2. How has technology improved the way criminal investigators perform their job?Technology improved the way criminal investigators perform their jobs by making it easier to track things, there is different types of software out there today to help them with these issues, and make the Jobs easier, when you have different technology to help. 3. Why would a company report or not report a compromise case? The reason a company may or may not report a compromise because If It's not in their favor and they may report It If It's In their favor and vice versa. They wouldn't want to look Incompetent. 4. Who Is In charge of labeling a nd securing sensitive Information?The one In charge of labeling and securing sensitive information is the forensic specialist. 5. What is the Daubers standard? The Daubers Standard provides a rule of evidence regarding the admissibility of expert witnesses' testimony during united States federal legal proceedings. 6. Why would someone use a hex editor in a forensic investigation? The reason someone would use a hex editor in a forensic Investigation is if the suspect has deleted files and has overwritten them on his or her hard disk, you can always use a hex editor to view any data stored In (or deleted from) both files and disk sectors.A hex editor allows you to peek at the physical contents stored on a disk, regardless of he boundaries of files, directories, or partitions. 7. What is the largest known data loss incident to date? The largest known data loss incident to date Adobe systems, Inc – 10-3-2013, 8. What group runs tallboys? Open Security Foundation runs tallboys. 9. On the website Tallboys. Org, of the largest 20 incidents, how many of them were computer hacks as opposed to other Issues like stolen laptops and lost drives? 1% of the Incidents were computer hacks as opposed to the other Issues. 10. What built-Len Windows tool Is used to manage the Encrypted File System (FEES)? The certificates is was is used to manage the FEES.. . What is the presumption of innocence? All people accused off crime are legally presumed to be innocent until they are convicted, either in a trial or as a result of pleading guilty. This presumption means not only that the prosecutor must convince the Jury of the defendant's guilt, but also that the defendant need not say or do anything in his own defense.If the prosecutor can't convince the Jury that the defendant is guilty, the defendant goes free. 2. The presumption of innocence, coupled with the fact that the prosecutor must prove the defendant's guilt beyond a reasonable doubt, makes it difficult for the overspen t to put innocent people behind bars. 3. What is hearsay and provide an example when Computer evidence can be considered hearsay? â€Å"Hearsay' refers to statements made outside of court of law an example of Computer evidence that is considered hearsay is 4.What is system integrity? System integrity is the state of a system where it is performing its intended functions without being degraded or impaired by changes or disruptions in its internal or external environments 5. What skills are required by an expert witness? The skills required by an expert witness are: A background in law, law enforcement, or investigation. A membership in professional associations of computer forensic examiners, formal training, and certification. A thorough knowledge of the subject matter and tools.Investigators must understand the kind of potential evidence they sought and analyzed and understand the tools they used to gather and preserve evidence. They should be accurate, truthful and impartial. 6. Locate and read the opinion Daubers v. Merrill DOD Pharmaceuticals. What was the case about? The Daubers v. Merrill DOD Pharmaceuticals was about two children ho had been born with birth defects and their parents sue Merrill DOD Pharmaceuticals Inc, claiming that the drug Benedictine caused the birth defects. 7. What was the outcome of the case?The district court granted summary Judgment for Merrill DOD, and Daubers and Schuler appealed to the Ninth Circuit. 8. What previous Supreme Court ruling was superseded by the Federal Rules of Evidence as the standard for admitting expert scientific testimony? The previous Supreme Court ruling was superseded by the Federal Rules of Evidence as the standard for admitting expert scientific testimony was the Fryer's â€Å"general acceptance† Daubers puts the responsibility of the admissibility of evidence by placing the Judge in the role of â€Å"gatekeeper†.

Hills Like White Elephants by Ernest Hemingway Essay

Ernest Hemingway’s, â€Å"Hills Like White Elephants†, was first published in August of 1927 but it was not until briefly after the lone publication of this esoteric short story that it received the notability it deserved; accompanied by many other encapsulating short stories, â€Å"Hills Like White Elephants† in addition to the thirteen other short stories published by Hemingway in October of 1927 made up his second collection of short stories, â€Å"Men Without Women†. Nevertheless, William Shakespeare’s, â€Å"Hamlet†, was the longest play ever written by the Englishman estimated to be written sometime within the late 16th and early 17th century; â€Å"Hamlet† is revered not only as one of Shakespeare’s greatest literary work but also as one of the most†¦show more content†¦This is notable in the conversation between the two as a child’s life figuratively depends on the outcome of this brief un-honest conversa tion, which is assumably another intended message by Hemingway directed at perceptive readers of his short story. As mentioned, the absurdity of the conversation between the two lovers is present within their communication, but this also displays the absurdity of the human condition as both characters lack the honesty to be frank or straightforward with each other. This trait is not only common within the victorian conservatism of the 1920’s and 1930’s but also in the present day. The subtly in which Hemingway stresses the dishonesty between â€Å"The American† and â€Å"Jig† is apparent in the retraction of the observation made by â€Å"Jig†. When â€Å"Jig† says, â€Å"They’re lovely hills† and â€Å"They don’t really like look like white elephants. I just meant the colouring of their skin through the trees† it is obvious by this statement that her emotions or opinion regarding abortion have changed (â€Å"Jig † is now considering keeping the child). Typical of his character, â€Å"The American† suggests the two should have another drink, plainly ignoring or not paying any attention to the opinion of â€Å"Jig† (which is another effort of Hemingway’s to show the couples inability to communicate truthfully). Alcohol plays a less important role in the absurdity of â€Å"Hills Like White Elephants†; however, it is still a strong metaphor forShow MoreRelatedHills Like White Elephants by Ernest Hemingway580 Words   |  2 PagesE.B. White once said, â€Å"Theres no limit to how complicated things can get, on account of one thing always leading to another.† This quotation means that nobody ever knows how complicated things are going to get, and on top of that they can get worse. One can agree with this statement because in life you can go through unexpected situations that really affect your life in a negative way, and in life things might get worse. Bo th Soldiers home by Ernest Hemingway and Hills like white elephants by ErnestRead More`` Hills Like White Elephants `` By Ernest Hemingway886 Words   |  4 Pagesreader could put themselves into. Whether they choose to partake in a wayward journey full of adventure or the daily life of a human being with morals; a story’s aspect influences those thoughts with a deeper understanding. In Ernest Hemingway’s â€Å"Hills Like White Elephants,† it follows an American man and girl at a resting point during their travels. They arrived by train, stopping between Barcelona and Madrid. While there, they patiently waited for the next train at a bar inside of the station.Read MoreHills Like White Elephants By Ernest Hemingway893 Words   |  4 Pages Ernest Hemingway was a prolific writer. His short story, â€Å"Hills Like White Elephants† shows the tense situation between a man and a woman on vacation. Hemingway chooses to be vague in many ways. He never gives real names to his characters, nor explicitly states where they are besides hinting that they are in Spain. Additionally, he leaves it entirely to the reader to discover what the couple is discussing. By only providing information to the reader through only the dialogue of the two centralRead More`` Hills Like White Elephants `` By Ernest Hemingway939 Words   |  4 PagesThe short story â€Å"Hills Like White Elephants† written by Ernest Hemingway, is an intriguing literary work that foretells the story of a man and a woman waiting for a train, whilst discussing their feelings and emotions towards the surgical operation that is about to occur on the woman. Although the story was originally written in August 1927, the piece was later published in Hemingway’s short story collection ‘Men Without Women’. The text includes a wide variety of literary terms and has various criticalRead MoreHills Like White Elephants By Ernest Hemingway990 Words   |  4 Pages Another relationship coming to an end†¦ Throughout the story â€Å"Hills Like White Elephants† written in 1927 by Ernest Hemingway, he used the train station setting, the desired operation, and obviously the relationship between the American and the girl to symbolize a crumbling relationship and unwanted gift between them. The American and the girl find themselves wound up in a rough, unplanned situation that they are trying to fix. Many bread crumbs are dropped throughout the story to symbolize a collapsingRead MoreHills Like White Elephants By Ernest Hemingway1446 Words   |  6 PagesErnest Hemingway’s short story â€Å"Hills Like White Elephants† explores the topics of abortion, sex before marriage, and feelings of separation. There are many different points of view one can take on Hemingway’s work. The main literary analysis that will be explained is the significance of the title and how it is layered into the story in various places. In addition to this, the narrator’s point of view will also be discussed since it plays a role in bringing the characters together. Lastly, it willRead More`` Hills Like White Elephants `` By Ernest Hemingway1750 Words   |  7 PagesErnest Hemingway’s stories are known for their ever interpreting meanings behind them, and â€Å"Hills Like White Elephants† does not trail from the rest due to the never mentioned word ‘abortion’. â€Å"Hills Like White Elephants,† written by Ernest Hemingway, takes place around World War 1 in Spain, at a train station (Hills Like White Elephants. 4). An American man and a girl have been discussing the girl’s unspecific operation. It is apparent that the girl is perturbed about this operation, while theRead MoreHills Like White Elephants By Ernest Hemingway1037 Words   |  5 PagesOlivia Sellers English 102 Scheck February 10, 2016 â€Å"Hills Like White Elephants† by Ernest Hemingway Ernest Hemingway’s â€Å"Hills Like White Elephants† can be puzzling and hard to decipher. Due to this, a number of conclusions can be drawn away from the text. The dialog between characters leaves a number of questions unanswered and leaves the reader confused about the conversation as a whole. Many things are left unsaid and not explained in the story, with that being the case, the reader must takeRead More`` Hills Like White Elephant `` By Ernest Hemingway865 Words   |  4 Pagesbefore it begins, or as easily getting rid of problem before it even became one. In the short story â€Å"Hills like White Elephant†, the compensation of abortion can easily be seen between Jig and her American lover’s decision whether to keep the innocent’s life or not. Ernest Hemingway uses the fiction element plot, symbolism, and setting to illustrate the theme of abortion in â€Å"Hills like White Elephants.† Abortion has been viewed as a crucial struggle between couples. Many view this situation as endingRead MoreHills Like White Elephants, by Ernest Hemingway1432 Words   |  6 Pagesunderstood behaviors. Ernest Hemingway weaves both of these stereotypes into his short story â€Å"Hills Like White Elephants.† The story’s plot revolves around a couple arguing about whether or not to have an abortion. In Hemingway’s â€Å"Hills Like White Elephants† a theme of male domination can be found, but by examining the dialogue closely, a theme of females asserting their will and manipulating emerges as well. Male domination is the primary and most obvious theme in â€Å"Hills Like White Elephants.† During the