The Pathogenesis of Atherosclerosis

The Pathogenesis of Atherosclerosis According to the World Health Organization, cardiovascular diseases are the leading cause of death worldwide, accounting for approximately 30 of all global deaths in 2008. A large proportion of CVDs is attributable to atherosclerosis, which is a major cause of myocardial infarction or stroke (1). The pathogenesis of atherosclerosis Over the past two decades, the inflammatory hypothesis of atherosclerosis has gained strong footing through multiple lines of supportive evidence (reviewed in (2)). Nowadays, atherosclerosis is considered a complex chronic inflammatory disease of medium- and large-sized arteries. Atherosclerosis occurs predominately at sites of disturbed laminar flow, in particular, arterial branch points and bifurcations. Human and animal studies indicate that the key initiating step is subendothelial accumulation of apolipoprotein B-containing lipoproteins (apoB-LPs). ApoB-LPs are secreted by the liver as very low-density lipoproteins, which are converted in the circulation to atherogenic low-density lipoproteins (LDL). In addition, apoB-LPs are secreted by the intestines as chylomicrons, which are converted by lipolysis into atherogenic particles, called remnant lipoproteins (3). Subendothelial apoB-LPs are believed to initiate an early inflammatory response, which may be enhanced by oxidative modification of LPs, through activation of overlying endothelial cells in a manner that leads to the recruitment of monocytes. Activated endothelial cells express adhesion molecules (e.g. intracellular adhesion molecule-1 and vascular adhesion molecule-1) and secrete cytokines and chemoattractants, or chemokines (e.g. monocyte chemoattractant protein-1 and RANTES), that act on monocytes and promote directional migration towards and into the artery wall. Once resident in the arterial intima, monocytes acquire the morphological characteristics of macrophages and increase their expression of scavenger receptors, including scavenger receptor A and CD36. Excessive uptake and internalization of modified lipoproteins via their scavenger receptors leads to the accumulation of cholesteryl esters in cytoplasmic droplets. These lipid-laden macrophages, known as foam cells, characterize the early atherosclerotic lesion (figure 1). As the atherosclerotic lesions further develops, macrophage and foam cells predominate, and further serve to alter the plaque environment, changing extracellular matrix composition and decreasing smooth muscle cell content, predisposing to plaque rupture (2, 4). Atherosclerosis and high-density lipoprotein therapy Although the development of atherosclerosis is dependent on a complex interplay between many factors and processes, a clear association has been established between elevated levels of plasma cholesterol and increased atherosclerotic disease (6). To attenuate the risk of atherosclerotic complications, primary and secondary prevention strategies seek to correct aberrant blood cholesterol levels. Actively reducing low-density lipoprotein (LDL) cholesterol through lipid-modifying therapies, such as statins, yield a proportional decrease in CVD risk (7). However, despite their potency, only 25-50% of cardiovascular events are prevented with highly potent statins, which highlights the importance of seeking for additional treatments for the optimal management of cardiovascular risk (8). Besides reducing LDL, improving HDL levels has gained a considerable amount of attention during the last decade. Epidemiological studies have shown that plasma levels of high-density lipoproteins (HDL) are inversely associated with clinical events resulting from atherosclerosis (9). Human and animal intervention studies have shown that increasing HDL results in a reduced atherosclerotic plaque size, suggesting that HDL may be an effective therapy for the regression of atherosclerosis (10). The mechanisms for plaque regression have been primarily attributed to the ability of HDL to promote cholesterol efflux from peripheral tissues, including macrophages, to the liver for excretion in the bile and feces. This process, called reverse cholesterol transport, is widely believed to account for much of the inverse relationship between plasma HDL levels and CVD revealed by population studies (11). HDL components can remove cellular cholesterol by four distinct processes. The presumed major precursor for this pathway is lipid-poor apoA-I, which is initially synthesized and secreted by the liver. Once in plasma, it rapidly acquires phospholipids and cholesterol from cell membranes in a reaction mediated by the ATP-binding cassette A1 (ABCA1) that results in the formation of pre-ÃŽÂ ² HDL particles (figure 2). A second mechanism involves ATP-binding cassette G1 (ABCG1), with pre-ÃŽÂ ² and large spherical HDL acting as the main acceptor. A third involves scavenger receptor B1 (SR-B1), which has the same acceptors as ABCG1. Lastly, cholesterol can be removed from cell membranes to HDL particles through passive diffusion. The latter three mechanisms are dependent on the presence and activity of Lecithin:Cholesterol AcylTransferase (LCAT). LCAT can esterify any unesterified cholesterol entering the outer surface of HDL, after which it will move into the intensely hydrophobic ce ntral core, leaving the outer surface of the HDL particle able to accept more unesterified cholesterol (12). Next to promoting cholesterol efflux, studies have shown that HDL is able to protect against cardiovascular diseases through a variety of additional functions, including anti-oxidant, anti-thrombotic, anti-apoptotic (reviewed in (12)). HDL has been shown to exert anti-inflammatory effects, which are mainly investigated in endothelial cells, and to a lesser extent in vascular smooth muscle cells (13, 14). Macrophages in the pathology of atherosclerosis It is generally accepted that macrophages play a pivotal role in the pathophysiology of atherosclerosis. The accumulation of macrophages and their conversion into foam cells, through the uptake of excessive amounts of lipids and cholesterol from modified apoB-LP, are considered hallmarks of atherogenesis. By expressing various effector molecules, including inflammatory cytokines, chemokines and extracellular matrix degrading enzymes, macrophages have a great impact on the activation, migration and survival of other cells in the plaque and ultimately affect plaque stability. However, within atherosclerotic plaques, macrophages represent a heterogeneous cell population, which may consist of several subsets that have distinct phenotypic and functional characteristics, ranging from large quiescent lipid-laden foam cells to a small active inflammatory cell. Furthermore, macrophages demonstrate a high degree of plasticity, which depend on the environmental cues they are exposed to. In gene ral, macrophages are skewed by interferon-ÃŽÂ ³ or lipopolysaccharide towards a pro-inflammatory or M1 phenotype, which produce mediators that have a pro-atherogenic effect. On the other hand, anti-inflammatory or M2 macrophages are polarized by interleukin (IL)-4, IL-10 and IL-13, which are believed to be of an anti-atherogenic nature. A phenotypical distinction can be made between these subsets based on their differential expression of cell surface expression (15, 16). High-density lipoproteins in modulating macrophages To date, HDL is considered to be the good cholesterol, because of its protective effects in atherosclerosis, such as anti-inflammatory properties (14). However, the effects of HDL on macrophages, which are major players in atherosclerosis, have yet to be established. The majority of the research conducted on the effects of HDL on macrophages have mainly been performed on cholesterol- or lipid-loaded macrophages. Here, HDL exerts anti-inflammatory effects by decreasing NF-ÃŽÂ ºB activation and secretion of pro-inflammatory cytokine, including tumor necrosis factor ÃŽÂ ± (TNFÃŽÂ ±), while increasing anti-inflammatory cytokines, like IL-10. To date, however, it is not known how HDL affects non-cholesterol or -lipid-loaded macrophages. Cholesterol is an important structural lipid that modulates Perturbations in cellular cholesterol levels has been shown to affect NF-ÃŽÂ ºB is an essential regulator of inflammatory processes in mammalian cells, including macrophages. When the NF-ÃŽÂ ºB pathway is activated, NF-ÃŽÂ ºB translocates to the nucleus and activates transcription of its target genes, including genes involved in cytokine production and secretion (17). In addition to NF-ÃŽÂ ºB, A Disintegrin And Metalloproteinases (ADAMs) are also implicated in numerous cellular processes, including inflammation. ADAMs are a group of enzymes that cleave the extracellular domains of various cell surface molecules, of which ADAM 10 and 17 are the best studied family members. ADAM 10 and 17 are closely related proteases and share many substrates, including TNF-ÃŽÂ ± and its receptor. ADAM activity can be regulated at various levels, including localization within the plasma membrane, where lipid rafts are thought to play a role in. Lipid rafts are cholesterol- and sphingolipid-enriched microdomains within the cell membrane, which are able to include or exclude proteins to variable extents. This dynamic process regulates protein interactions and influences their functions. Lipid rafts can be decreased and disrupted by cholesterol depletion, e.g. by HDL (18). Tellier et al. showed in vitro that TNFÃŽÂ ± shedding was increased in fibroblasts and ECs after incubation with HDL. This was attributed to an increased activity of ADAM 17, which was due to lipid raft disruption by cholesterol depletion (19). Study aim and design The purpose of this study is to investigate the effects of HDL on macrophage phenotype and whether NF-kB signaling, lipid raft disruption and increased activity of ADAM10 and 17 are involved in this. First, we will determine the effects of HDL on M1 and M2 macrophage polarization by exposing bone marrow-derived macrophages (BMDMs) from C57BL/6 mice to HDL. Here, M1 and M2 polarization markers will be determined using quantitative PCR and ELISA. Second, we will examine whether NF-ÃŽÂ ºB signaling is involved in the pro-inflammatory effects induced by HDL in macrophages. Lastly, we will investigate whether HDL skews macrophages towards a pro-inflammatory state by increasing ADAM10 and 17 activity through lipid raft disruption. activity assay We hypothesize that HDL polarizes macrophages towards a pro-inflammatory phenotype due to activation of the NF-ÃŽÂ ºB signaling pathway and an increased ADAM10 and 17 activity, through lipid raft disruption Literature 1. Mendis S, Puska P, Norrving B, editors. Global Atlas on Cardiovascular Disease Prevention and Control. Geneva: World Health Organization; 2011. 2. Wong BW, Meredith A, Lin D, McManus BM. The biological role of inflammation in atherosclerosis. The Canadian journal of cardiology. 2012;28(6):631-41. Epub 2012/09/19. 3. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arteriosclerosis, thrombosis, and vascular biology. 1995;15(5):551-61. Epub 1995/05/01. 4. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868-74. Epub 2002/12/20. 5. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011;145(3):341-55. Epub 2011/05/03. 6. Liao JK, Laufs U. Pleiotropic effects of statins. Annual review of pharmacology and toxicology. 2005;45:89-118. Epub 2005/04/12. 7. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7-22. Epub 2002/07/13. 8. Arsenault BJ, Kritikou EA, Tardif JC. Regression of atherosclerosis. Current cardiology reports. 2012;14(4):443-9. Epub 2012/06/19. 9. Rader DJ, Alexander ET, Weibel GL, Billheimer J, Rothblat GH. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J Lipid Res. 2009;50 Suppl:S189-94. Epub 2008/12/10. 10. Linsel-Nitschke P, Tall AR. HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nature reviews Drug discovery. 2005;4(3):193-205. Epub 2005/03/02. 11. Oram JF, Heinecke JW. ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease. Physiological reviews. 2005;85(4):1343-72. Epub 2005/09/27. 12. Soran H, Hama S, Yadav R, Durrington PN. HDL functionality. Current opinion in lipidology. 2012;23(4):353-66. Epub 2012/06/27. 13. Bursill CA, Castro ML, Beattie DT, Nakhla S, van der Vorst E, Heather AK, et al. High-density lipoproteins suppress chemokines and chemokine receptors in vitro and in vivo. Arteriosclerosis, thrombosis, and vascular biology. 2010;30(9):1773-8. Epub 2010/08/13. 14. Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circulation research. 2004;95(8):764-72. Epub 2004/10/16. 15. Stoger JL, Goossens P, de Winther MP. Macrophage heterogeneity: relevance and functional implications in atherosclerosis. Curr Vasc Pharmacol. 2010;8(2):233-48. Epub 2010/02/26. 16. Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation and polarization. Frontiers in bioscience : a journal and virtual library. 2008;13:453-61. Epub 2007/11/06. 17. Gilmore TD. Introduction to NF-kappaB: players, pathways, perspectives. Oncogene. 2006;25(51):6680-4. Epub 2006/10/31. 18. van der Vorst EP, Keijbeck AA, de Winther MP, Donners MM. A disintegrin and metalloproteases: Molecular scissors in angiogenesis, inflammation and atherosclerosis. Atherosclerosis. 2012;224(2):302-8. Epub 2012/06/16. 19. Tellier E, Canault M, Poggi M, Bonardo B, Nicolay A, Alessi MC, et al. HDLs activate ADAM17-dependent shedding. Journal of cellular physiology. 2008;214(3):687-93. Epub 2007/09/06.

Physical and Emotional Burdens Essay

In The Things They Carried, O’Brien talks about multiple different things that the men at war carry. They take things with them that soldiers always have like guns, bags, grenades, ammo, food, water, and things like that, but they also carry personal items like Kiowa’s Bible and moccasins, or Jensen’s vitamins. The men however, have more than just physical items. They have things that always stay with them like emotional and figurative things. Throughout the novel, O’Brien goes back to the theme of things carried, whether that be in necessities, superstitious items, or emotional burdens. O’Brien uses the first chapter to explain, in detail, the physical things that the men carried. He tells of how the men take their, â€Å"compass, maps, code books,† (O’Brien 5) along with â€Å"the M-60, M-16, M-79 – they carried whatever presented itself, or whatever seemed appropriate as a means of killing, or staying alive.† (7). These young men at war put anything that can possibly help them in their bags. Even if it is not necessary for the specific mission they are on, they take these items with them because of their collective fear of the unknown. Their cumbersome, bulky, heavy backpacks and gear weigh on the men physically, and also as shown throughout the book, take a toll on their morale. O’Brien uses this style of writing and the theme as a tool to impress upon his audience just how heavy the burdens of the men really are. The longer they have to carry all these things the worse it got. The physical items that they lug with them are not limited to items issued by their generals. Many of them also carry superstitious things that they think might help throughout the war. Jimmy Cross has his, â€Å"good-luck charm from Martha. It was a simple pebble† (6), and â€Å"Dobbins carried his girlfriend’s pantyhose wrapped around his neck† (9), and Kiowa â€Å"always took along his New Testament and a pair of moccasins† (9). Whether it is to comfort them, or for religious purposes, or just plain superstition, most of them have some sort of personal item that they take along with them. Even though they already have hundreds of pounds of equipment to carry, they still choose to carry these things. This is very justifiable however, because most of these items are something from home, something to remind them of what they have back home, and gives them hope that they will someday return there. Hope is a present theme in The Things They Carried, and is always necessary with men at war, because without hope they would have nothing to fight for and their morale would be gone. The most burdensome of things carried by the men, is the emotional baggage. Throughout the novel, Lieutenant Jimmy Cross carries the emotion of love. This weighs on him an enormously throughout the war because he can never get his mind off of Martha, even though she does not love him back. This causes emotional detachment from the war and from commanding his troops. When Ted Lavender dies, Cross blames himself for not being as focused as he should be because of Martha, and burns her pictures and letters. Even though he no longer physically carries these things, he still emotionally carries them throughout the book because he can never get them out of his mind. Kiowa is another example of one of the soldiers who carries an emotional burden with the tremendous weight of â€Å"his grandmother’s distrust for the white man† (3). This could propose a difficulty to trust his fellow soldiers. All the men carry with them the memories of their fallen friends and fellow soldiers. They find different ways to grieve over the fallen soldiers, but never do forget them. Like O’Brien says, â€Å"The thing about remembering, is that you don’t forget.† (33). These young men fighting for their country in Vietnam are extremely brave. War is a really hard thing for non-soldiers to comprehend when you start to  talk about the stories of what happened when they are just marching around the jungle. But the theme of emotional and physical things carried is heavily shown throughout the book and presents reasoning for why these men did and felt the things they did. Works Cited O’Brien, Tim. The Things They Carried: A Work of Fiction. New York, Boston: Mariner, 2009. Print.

Heroes and Villains Iago and the Extent of Human...

The character of Iago has traditionally been viewed as the most infamous villain in all of Shakespeare. The conniving ringmaster of the tragedy of Othello, Iago serves as a necessary catalyst for the action of the play. He takes such a principal role in the drama that the play has commonly been described as Othello’s tragedy, but Iago’s play. Scholars have disagreed, however, as to whether or not Iago can simply be described as an ingenious villain lacking all regard for morality. Many have seen some of his most inhuman or evil qualities as the very thing that makes him human; others have attributed his manipulative ambition to a deep-seeded psychological need to belong and have drawn clear parallels between Iago and the play’s tragic†¦show more content†¦Cassio affirms that he â€Å"never knew / a Florentine more kind and honest† (III.i.37-8). Othello immediately declares him to be â€Å"of exceeding honesty† (III.iii.257) and soon begins to unquestionably take the word of his acquaintance Iago over the word of his wife, Desdemona. Iago’s charisma and deep understanding of the other characters’ ambitions and weaknesses allows him to become the puppet master of the tragedy, initially predicting each character’s behavior with great precision. But as the action unfolds, however, Iago is increasingly unable to control his situation, and in his attempts to regain control he begins to improvise with murders, including that of his own wife. While his charisma and genius understanding of human nature allow him to set his devious plan into action, his overestimation of his own abilities traps him in â€Å"in the web he spins for others† and ultimately leads to his arrest and execution (Bradley 3157). Iago’s initial success in achieving his goals is representative of the extent of human potential in the play. While his plot stems from selfish and devious motives, Iago is wildly successful in achieving his goals up until the very end of the tragedy. His keen perceptions of the other characters’ natures allow him to exploit their weaknesses. He recognizes that Othello, as someone of â€Å"a free and open nature / that thinks men honest that but seem to be so† (I.iii.378-379), can be easily manipulated due to his deep trust inShow MoreRelatedDuchess Of Malf Open Learn10864 Words   |  44 Pagesout textual analysis recognise some of the historical contexts of the play. Background John Webster (c.1580–c.1634) was Shakespeare’s contemporary, though sixteen years younger. He makes a brief appearance in the 1998 film Shakespeare in Love as a boy who tortures mice, spies on Shakespeare’s love-making, and feels inspired to take up the pen himself after seeing Shakespeare’s blood-soaked revenge tragedy, Titus Andronicus. ‘Plenty of blood. That’s the only writing’, he asserts. This affectionateRead MorePlay Macbeth11979 Words   |  48 Pagesconvinces him to committ the first of his evil deeds. Macbeths evil deed causes him to suffer from fear and guilt, which leads to even more evil crimes. Then Macbeth becomes paranoid, suffering from hallucinations and sleeplessness. He becomes less human as he tries over and over to establish his manhood. His ruthlessness in killing Banquo and Macduffs family shows how perverted his idea of manliness really is. Macbeths degeneration is also seen in the collapse of his marital relationship. TheyRead MorePlay Macbeth11985 Words   |  48 Pagesconvinces him to committ the first of his evil deeds. Macbeths evil deed causes him to suffer from fear and guilt, which leads to even more evil crimes. Then Macbeth becomes paranoid, suffering from hallucinations and sleeplessness. He becomes less human as he tries over and over to establish his manhood. His ruthlessness in killing Banquo and Macduffs family shows how perverted his idea of manliness really is. Macbeths degeneration is also seen in the collapse of his marital relationship. They

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