138 Vol. 1. No. 3 September–December 2010 M E C H A N I S M S O F P E R I O D O N T I T I S - I N D U C E D ATHEROSCLEROSIS rikko Hudyono1 and Jenny sunariani2 1Department of Periodontology 2Department of Oral Biology Faculty of Dentistry, Airlangga University Surabaya - Indonesia abstract Nowadays CVD become the most common cause of death in US and worldwide. Atherosclerosis plays an important role in CVDs pathogenesis. Atherosclerosis decreases the elasticity of the vascular. Atherosclerosis shares the same risk factor as CVD, in which obesity, hyperlipidemia, hypertension and lack of physical activity may initiate it. However, 50% of all CVD patients are lack of the usual causes of CVD. The purpose of this review is to reveal the mechanism of periodontitis-induced atherosclerosis. Inflammation and autoimmune disease might play an important role in initiate the CVD. Periodontitis is one of the oral diseases which can cause systemic inflammation and may induce the atherosclerosis. Porphyromonas gingivalis (Pg) which is the major cause of periodontitis can induce it by expressing protein gp130 in its fimbriae. Periodontics patients are prone to have bacteremia by daily routine oral hygiene activity. Chronic bacteremia may alter the endothelial physiology, which is resulted in neointima formation, EC dysfunction, and lipid accumulation. It is concluded that periodontitis may play an important role in initiation and progression of atherosclerosis. Key words: Pg’s fimbriae, bacteremia, cytokines, endothelial dysfunction, atherosclerosis Literature Review introduction In the 20th century, due to developments and inventories in medical field, the human�s life expectancy was dramatically increased. There was a major shift in the causes of illness and death throughout the world. In 1950, infections were the most common causes of death. A century ago, CVD accounted for less than 10 percent of all deaths. Nowadays, CVD become the most common cause of death in US[1] and worldwide.[2,3] It causes global epidemic worldwide.[4] Approximately 30 percent of deaths worldwide are caused by CVD,[5] including nearly 40 percent in high-income countries and about 28 percent in low- and middle-income countries.[2] In 2006, it was reported that more than 81 million of US citizens got CVD.[6] Driven by industrialization, urbanization, and associated life changes; e.c smoking, high calories and lipid intake, these ongoing transition are occurring around the world of all races, ethnic groups, and cultures at an even faster rate than last centuries and may lead to cause CVD.[7] The risk of having CVD will increase in obesity, hypertension and impairment of lipid metabolism.[2,7] Atherosclerosis is mainly caused by decreasing in vascular elasticity and lumen.[8,9] Atherosclerosis is known to share the same risk factors as CVD, which obesity, hyperlipidemic condition, hypertension and lack of physical activity may initiate it.[8] However, 50% of all patients with CVD were lack of known risk factors.[10] Autoimmunity[11] and systemic inflammation[12-16] were supposed to be possible to play a role ini CVD�s initiation and progression. Infection and bacterial products may play an important role in atherosclerosis pathogenesis.[17,18] Immune response and inflammation factors, e.c. CRP, interleukin, and chemokines were suggested to be the causes and markers in atherosclerosis lesions.[19,20] Atherosclerosis had been proven to be induced by periodontopathogen from periodontitis.[21-28] Inflammation in mouth may cause systemic inflammation, which is indicated by the elevation of CRP in the body,[29,30] which is functioned as markers,[31,32] predictors of CVD,[33,34] and 139Hudyono and Sunariani: Mechanisms of periodontitis-induced may induce atherosclerosis lesions.[35–38] Focal infection in mouth may induce atherosclerosis lesions by initiate systemic and humoral immune responses.[39] Periodontopathogen bacteria may widely spread to another part of the body. Bacterial inoculation from atherosclerotic plaque have proven the presence of periodontopathogen bacteria such as Porphyromonas gingivalis, Actinobacillus actinomycetem comitans, dan Bacteroides forsythus.[39,40] This article reviews the current state of knowledge concerning the direct role of periodontitis in developing atherosclerotic lesions. Better understanding of these diseases and long-term research will be needed to rehabilitate these lesions in the future. literature review Periodontitis is defined as an inflammatory disease of the supporting tissues of teeth caused by specific microorganism or group of specific microorganisms, resulting in progressive destruction of the periodontal ligament and alveolar bone with pocket formation, recession or both.[41] Chronic periodontitis is the most common form of periodontitis, which is associated with plaque accumulation. It generally has a slow to moderate rate of disease progression, but periods of more rapid destruction may be observed. Systemic disease such as diabetes mellitus and HIV infection may influence the host defenses, and environmental factors such as cigarette smoking, and stress also may influence the response of the host to plaque accumulation.[41–44] Although many factors may influence the onset of periodontitis, periodontopathogen bacteria play a key role in the onset and severity of periodontal diseases.[42,45,46] PG is an anaerob obligat,[47] non-motile,[48] pleiomorphic bacteria, and posses a capsul.[49] PG shows a strong proteolitic activity, grows in anaerobic environment, and shows dark pigmentation (brown, dark green, or black) on blood agar.[50] PG has fimbriae[51] which mediates adhesion.[52] The capsul serves a protection to prevent it from phagocytosis53 and triggers the secretion of IL-1, IL-6, dan IL-8.[48] The end products are various kinds of amino acid and endotoxin, haemolysin, collagenase and proteases which may damage immunoglobulins, complements, and heme- sequestering proteins: a protein which inhibits collagenase activities.[42,53,54] PG was shown to be able to invade epithelium,[51] soft tissue, inhibit PMN cell migration across the epithelium[55] and may cause cytokine degradation in mammal cells.[42,53] physiology of Blood Vessels Arteries are strong, elastic vessels that are adapted for transporting blood away from the heart under high pressure to all parts of the body.[56] These vessels subdivide into progressively thinner tubes and eventualy give rise to the finer branched arteriolles.[56] The wall of an artery consists of three distinct layer, or tunics; tunica adventitia, tunica media and tunica intima as the innermost layer.[57-59] Tunica adventitia is the outermost layer of the arterial wall. Researches were conducted, as it was known to have a potential role in homeostasis and pathological effects on the artery.[8] This outer layer is thin and chiefly consists of irregular connective tissue[57] and collagenous fibers.[8] Vasa vasorum and nerve endings are usually located on this outermost layer. This layer attaches the artery to the surrounding tissues.[57] Cell populations in this layer are relatively rare compared with those in the other layer.[8] This layer mainly consists of fibroblast and mast cell.[8] In clinical research with animal, this layer was suspected to induce atheroma and aneurysm lesions.[8] Tunica media, located between tunica intima and tunica adventitia, is the thickest layer of the arterial wall.[57] The artery, especially the aorta, is surrounded by tunica media, which has SMC layer[57] and elastin as the extracellular matrix.[8] This structures make the artery very elastic and enable it to withstand against the force of blood pressure, and at the same time, tp stretch and accommodate the sudden increase in blood volume that accompanies ventricular contraction.[57] These structures are also important in maintaining the integrity of arterial branches.[8] On the smaller artery; where the SMC in tunica media are not as strong as those in aorta; elastin are arranged in continuous layer, not in circular around the vessel wall.[8] On the capillaries, the tunica media becomes very thin, only single cell thick with some SMC�s cells.[57] Tunica intima is the innermost layer of the arterial wall.[8] The wall is covered with simple squamous epithelium attached to the basal lamina, fibrous connective tissue which is rich in elastic and collagen fibers,[57] known as endothelium.[56] In all newborn species, tunica intima is very thin.[8] However, in adult, its structure becomes more complicated and heterogen.[8] Thin endothelial layer is attached to basalis membrane which is contain non-fibril collagen e.c collagen type IV,[8] proteoglycan (chondroitin and dermatan sulphate), elastin, protein plasma,[9] laminin, fibronectin, and the other extracellular matrixes. As becoming older, the intimal layer will be developed more complicated, where it will be contained SMCs and fibril interstitial collagen, like tipe I and III. The more complex intimal layer are known as intimal thickening, which is the common characteristic in adult�s vessels.[8] Endothelial cells (ecs) ECs are the most important cells in tunica intima because they are fundamental to the maintenance of vessel wall homeostasis and normal circulatory function.[8,58] The endothelial lining of an artery provides a smooth surface that allows blood cells and platelets to flow through without being damaged.[57] ECs have five major role: 1) it is a metabolicaly active secretory tissue;[58] 2) to provide a smooth surface in the artery and secrete some anti- coagulants and anti-thrombotic agents;[8,57] 3) as a barrier 140 Indonesian Journal of Tropical and Infectious Disease, Vol. 1. No. 3 September–December 2010: 138-145 to the indiscriminate passage of blood constituents into the arterial wall;[58,61] 4) to help in controlling growth and elasticity of the vessels;[61] and 5) to adjust the vascular tone by strictly regulating the paracrin and autocrine.[61] ECs may release vasoactive factors, which control the lokal vessel constriction and dilatation.[58] The vasodilator includes nitric oxide, prostacyclin, EDRF, and EDHF; and the vasoconstrictor includes endothelin, prostanoids and angiotensin II.[58,59,61] ECs are also able to secrete some procoagulants agents as factor VII, factor Va, factor von Willebrand�s, tissue factor and PAI-1;[58,61] and also some fibrinolitic agents as thrombomodulin, tissue plasminogen activator, heparin sulfate proteoglycan, which acts like heparin as a co-factor for antithrombin III, a coagulation- inhibitor by binding and inactivating thrombin.[8] NO is known as a potent EDRF[58] which inhibits vasoconstrictors� effects.[8] NO is also inhibit platelets aggregation and adhesion, leukocyte infiltration and adhesion, and also SMCs� migration and proliferation.[59] NO is also able to prevent LDL oxidation.[61,62] NO is produced in ECs by oxidating guanadino nitrogens L- arginine[58,61] which is catalyzed by eNOS enzyme in caveolae.[62] The presence of caveolin-1 proteins, which will bind the calmodulin, will inhibit the eNOS activity. Chemically bond of Ca2+ ion and calveolin will substitute caveolin-1 and thus increases NO production.[59,62] Some co factors like NADPH,[59,62] BH4, [58,63] flavin nucleotide and oxygen molecule[64] are needed in NO synthesis. BH4 is needed in electron transfer process from heme enzyme group in L-arginine to produce NO.[59,62] In the atherosclerotic lesions, endothelium might be altered structurally and functionally. ECs may be more permeable to lipoproteins, hyperadhesive to leukocyte cells, and alter their homeostasis function in producing local pro- and antithrombotic, growth factor stimulator and inhibitor, and also vasoactive enzyme. These alterations are known as endothelial disfunctions, which have a big impact in initiation, progression and complications of atherosclerotic lesions.[9,60] smooth Muscle cell (sMc) SMCs have a lot of function in maintaining normal homeostasis vessels.[8] SMC�s are responsible for vasoconstriction and dilation in response to normal or pharmacologic stimuli, homeostasis mechanisms to deliver blood to all parts of the body.[56,57] The arteries have more SMCs than the veins do, which makes the arterial wall much thicker. SMCs are innervated by simpathic nerves through adrenoreseptor with norepinepineprine as endogenous agonis. They also synthesize collagen, elastin, and proteoglicans; and elaborate growth factors and cytokines; which may alter morphology, proliferation rate and cell migration on the vessel�s wall.[65,66] SMCs are involved in pathogenesis of atherosclerosis and become a target in cardiovascular management therapy.[8] In big arteries with atherosclerotic lesions, SMC�s contraction will cause vasospasm and impede the blood flow.[8] Normal SMCs synthezise a lot of extracellular matrix to maintain normal homeostasis, and prevent atherosclerosis.[65] Normally, SMC�s rarely proliferate. The rate of cell proliferation and necrosis are very low under the normal condition. Extracellular matrix will always be in homeostasis circumstances. Synthesis and dissolution are always the same rate; there will never be cell accumulation or atrophy.[8] Under the pathologic condition, the cells may proliferate and migrate; thus may induce hyperplastic lesions such as atherosclerosis and re-stenosis.[8] SMCs� migration and proliferation are stimulated by PDGF, endothelin-1, thrombin, FGF, IFN-g, and IL-1. On the contrary, NO, heparin sulphate and TGF will inhibit this process.[66] atherosclerosis Atherosclerosis is disease where the artery loses its elasticity.[9,55,56] Atherosclerosis was defined as a chronic immunoinflamatory, fibroproliferative, disease which have been drived by lipids.[9] It affects primarily the intima of medium-sized and large arteries, resulting in intimal thickening, and may lead to luminal narrowing and inadequate blood supply.[9] Endothelial disfunction is the main cause of this disease.[56] Atherosclerosis forms atherosclerotic plaques,[56,66] which in turn, will cause lumen narrowing,[9] and obstruction;[66] weaken the big and medium-sized arterial structure;[9] impede the blood flow;[56] and reduce its elasticity.[56] As the name implies, mature atherosclerotic plaques consist typically of two main components: one is lipid-rich and soft (athére is Greek for ‘gruel� or ‘porridge�) and the other is collagen-rich and hard (skleros is Greek for ‘hard�).[9,66] The flow-limiting potential of an intimal plaque may be modified by reactive changes in the underlying media and adventitia that may be attenuate (positive remodeling) or accentate (negative remodeling) the luminal obstruction and consequent hemodynamic impact of the plaque.[9] Furthermore, enhanced vasoconstriction and reduced vasodilator capacity associated with atherosclerotis can further contribute an additional dynamic component to luminal obstruction.[9] The aggregation of lipoprotein on the tunica intima is considered as the early step of atherosclerosis. On this early step, atherosclerosis will apparent as a fatty streak consists of foam cells filled with lipid.[8,9,60,66,67] Lipoprotein will bind proteoglycan on the tunica intima where it will be stabilized on this layer. Proteoglycan-binded lipoprotein will be oxydated easier and undergo chemically alterations which were believed to be the early pathogenesis of atherosclerosis.[8,9] The other researches showed that the increasing of endothelial permeability mainly caused LDL aggregation in the intima.[9] Some factors, i.e NADH/NADPH oxydase which is released by vascular cells; lypoxigenase that is released by infiltrating leukocytes; and myeloperoxidase may cause oxidative stress in the atheroma.[9] Atherosclerosis lesions is also composed of leukocytes accumulation as a result of endothelial dysfunction.[8] Normal endothelial cells are able to prevent leukocytes 141Hudyono and Sunariani: Mechanisms of periodontitis-induced adhesion on their surfaces.[56] Eventhough in the inflamed area, leukocytes infiltration is started in venous, not in the artery.[9] In hypercholesterolemic condition, leukocytes adhere on the endothel and have a diapedisis on the EC junction into the tunica intima, where these leukocytes start lipid accumulation and become foam cells.[9,66] Besides the monocytes, lymphocytes T also tend to accumulate in atherosclerotic lesion in human and animals.[8,9] Accumulation of monocyte and lymphocyte T were stimulated by leucocyte adhesion melocule secreted by EC surfaces.[8,9,66,68] discussion In many epidemiological studies, periodontitis was proven to play important roles in initiation and progression of CVD,[69,70] by chronic infection on the blood vessels[20–29] or by the elevation of body�s CRP level.[29–39] The prevalence of chronic periodontitis was very high among populations, especially in chronic form.[41–44,69–72] Chronic periodontitis is usually neglected and undetected, because it is lacked any clinical signs and symptoms.[41,42,71] In chronic gingival and periodontal infection, the cappilarries are more fragile, which make it possible for microorganisms in plaque and calculus to be spread along with blood flow.[73] Chronic bacteremia from periodontitis may be easily happened from the daily activities e.c brushing, chewing,[73] and routine dental procedures like scaling and root planning, or the other treatments like endodontic, orthodontic and dental extraction.[74] Many studies proved that atherosclerosis plaques contained numerous periodontopathogen bacteria,[3,40,76] especially PG.[39,40] Researches have demonstrated that PG induction may invade endothel and may initiate atherosclerosis in pigs.[75] The presences of PG in atheroma and human carotid aorta had been detected by immunostaining and PCR.[76,77] PG was known to have fimbriae, which allowed it to invade[51] and stimulate host response to produce citokynes,[52,78-81] and may be in latent phase[82] to cause chronic infection in EC and SMC.[75] Chronic infection was known to be able to cause endothelial dysfunction.[21–38] PG�s fimbriae secretes protein, called gp130,[83] which facilitate PG to invade EC and trigger celluler immune response.[84] The host will secrete TNF,[85] IL-1, IL-6, IL- 10, and IL-12[86–88] by TLR�s stimulation.[26,85,88–90] TLR is part of immune system, which will respond to PAMP.[91] Protein in PG�s fimbriae may act as PAMP which triggers immune response by activating TLR, which, hence stimulate the host to produce cytokines.[86,91] tunica intima thickening Atherosclerosis may emerge from physiologic changes in EC. In early phase, atherosclerotic lesions is started by thickening of tunica intima (neointima).[8] Epidemiologic studies reported a positive relationship between PG infection and the formation of neointima.[92] Mechanism of PG infection and neointima thickening was remained unclear. It was supposed that TNF stimulation by protein gp130[83] might facilitate lymphocyte and monocyte adhesion[85] and also stimulate cytokines and growth hormone in host cells.[86–93] Neointima formation is mainly caused by accelerating proliferation rate, inhibiting apoptotic process, and increasing SMC migration to the neointima layer.[8] In EC, PG invasion may accelerate TNF[94] and IL-6 synthesis,[68] which in turn may initiate atherosclerosis lesions by accelerating SMC proliferation,[68] stimulating tissue factor,[95] increasing platelet aggregation[95] and increasing the level of fibrinogen in blood.[93] TNF may initiate neointima hyperplation through p55 pathway.[94] TNF was also known to induce FGF and NFkB secretion, SMC proliferation and neointima formation.[96] NFkB may inhibit apoptotic process[97–99] by suppressing the activity of gen p53,[100] which is responsible to induce the apoptotic process.[101] Its mechanism was remained unclear, but it was assumed to have the same mechanism as gen IE from CMV. Gen IE was able to bind gen p53 and disturb transcription process by extracting this gen from nucleus by cytoplasmic sequestration process.[102] Growth hormone, from TNF induction may increase proliferation rate.[96] Rupture endothel will secrete MCSF,[103,104] which will increase fibroblast proliferation rate, increase the production of IL-1,[105] induce the synthesis of vasoactive factors, growth factor, vascular adhesion molecules, and chemokines.[106] Infection may increase the production of FGF and PDGF almost twice higher.[68] MCSF and IL-1 induction in proliferation process of fibroblast and SMC were supposed to be performed via cyclooxygenase pathway.[68,107] The formation of neointima mass is also caused by SMCs migration from tunica media and tunica adventitia into the tunica intima.[8–10] Infections may increase PDGF reseptors sensitivity which result in SMC thickening in tunica intima. Besides FGF and PDGF, there some factors are known to play roles in SMC migration, they include endothelin-1, thrombin, IFN-g, TGF and IL-1.[8,9,58,59,61,66] Whereas NO, heparat sulphate, and TGF-b will act as antagonists to inhibit SMC migration.[8,9,61,62] Injured ECs[68] and the presences of either TNF[108] or CRP[109] may trigger the synthesis of cell adhesion molecules e.c VCAM-1 and ICAM-1.[68] VCAM-1 will interact with VLA-4, which is exclusively sinthezised by monocyte, T cell, and leukocyte accumulated in atheroma.[8] VCAM will facilitate monocyte adhesion[8] and infiltration into injured arterial wall and may increase SMCs proliferation rate.[66,109] ICAM-1 is immunoglobulin secreted by ECs surfaces. The role of this molecule is remained unclear as it is produced only in very small amount, and the leukocyte which will be bound is remained unknown.[8] It was supposed that ICAM-1 will increase VCAM-1 production.[110] Once the leukocyte binds the EC, it needs a signal to penetrate into EC and enter the arterial wall.[8] Leukocyte 142 Indonesian Journal of Tropical and Infectious Disease, Vol. 1. No. 3 September–December 2010: 138-145 migration would be impossible without the presence of protein molecules known as chemoattractant cytokine or chemokines. At the early phase of atherosclerosis, chemokines attract monocyte into the atheroma.[8] MCP-1 facilitate monocyte chemotactic into the arterial wall.[8,66] MCP-1 is a kind of chemokines produced by ECs as a response to CRP,[111] MCSF,[68] and oxidized lipoprotein, and the other stimulus.[112,113] The disturbances in local blood flow may result in some physiologic changes, which are responsible for predilection lesion of atherosclerosis.[8,9,58,66] Atheroma may act as an obstacle in local blood flow and causes local blood turbulances that will inhibit ECs to produce superoxide dismutase enzyme and eNOS, which are known to have a protective effect against the atherosclerosis.[58,62,66,101] Superoxide dismutase enzyme is able to reduce oxidative stress by catalyzing catabolic reaction on reactive superoxide anion into oxygen and hydrogen peroxide, where this hydrogen peroxide will be converted to be water and oxygen.[58,101] eNOS produces NO as an endogenous vasodilator.[62] Besides as vasodilator, it also suppresses VCAM-1 production from inflammation-induced ECs.[8,114] NO may also act as anti-inflammatory agent by increasing IkBa production,[115] an intracellular inhibitor, which will disturb the NFkB transcription process.[8,115,116] NFkB regulates various genes, which are responsible in inflammatory process and especially in atherosclerosis.[8,114-116] Endothelial dysfunction Prolonged infection in blood vessels may result in endothelial dysfunction.[8-10,17,59-62] Normal ECs posses an antithrombotic effect, which make them able to release and synthezise substances as heparin sulphate PGI2 , NO, plasminogen activator, and thrombomodulin.[8,9,59-62] Infectious agent may change ECs phenotype, from anticoagulant in usual, to be procoagulant.[8-10,62,66,117] Bacteria and its product, endotoxin, may cause endothel to produce tissue factor which in turn it will activate extrinsic blood clotting cascade,[117] increase thrombin formation, and platelets aggregation and at the same time these infections may suppress the synthesis of PGI2, and thrombomodulin.[8,9] Inhibition of prostacyclin happened as the presence of CRP which is suppressed PGI2 production which may cause disturbance in TBB2/PGI2 ratio. [35] The disturbance in the ratio of TBB2/PGI2 may facilitate platelets aggregation.[35] The other important role of EC is to have a local vasodilatation.[8-10] A pilot study had demonstrated that infection might disturb local endothelial vasodilatation response. This dysfunction is mainly caused by the disturbance in NO and non-NO pathways. Disturbances in NO pathways automatically will increase platelet aggregation, leucocyte adhesion and SMCs proliferation.[61] Decreased NO production will increase LDL oxidation, where oxidated LDL may increase caveolin-1 production and inhibit NO synthesis by inactivating eNOS.[62] Macrophage is also able to produce ROS10 which will inactivate NO[118,119] and destroy BH4. [62] Vascular damage was believed to induce atherosclerosis and be responsible for its progression.[8–10,66] In in-vitro study, it was found that PG was able to adhere and invade on vascular wall,[52,78–81] which was indicated that PG may cause vascular damages.[82] Endothel damage may cause ECM, beneath it, become exposed. Platelets may have a direct contact to ECM on that area which makes them active.[117] Activated platelets will stimulate intrinsic pathway of coagulation cascade and activate fibrin-forming process.[117] lipid accumulation The presence of infection may facilitate lipid accumulation. Infection was known to be able to reduce cholesterol ester hydrolytic activity[120,121] and increase the scavenger reseptor susceptibility.[122] Infection on human SMCs may increase LDL oxidation mediated by scavenger reseptor. Foam cells accumulation and the level of cholesteryl ester will dramatically increase if infected macrophages are incubated in an area with a high LDL level.[122] ROS may cause LDL oxidation in arterial wall, and then the oxidated LDL,[62] mediated by scavenger receptor, will be absorbed by macrophage and form foam cells.[123] MCSF may increase cholesterol uptake by macrophage and delayed the apoptosis process, which may cause foam cells forming.[68] It was summarized that atherosclerosis may be periodontically induced. PG, one of the periodontopathogens, was supposed to induce atherosclerosis via bacteremia. Pg with its fimbriae may invade and stimulate various kinds of cytokines, which are caused neointima proliferation, endothelial dysfunction, and lipid accumulation. These were facilitated with endothelial physiologic switching that tends to be pro-thrombotic; lipoprotein accumulation, especially LDL; chemically altered LDL via oxidation; monocytes and platelets adhesion on the vessel�s wall; and also the inflammation factors released from platelets and macrophages. This review was not subjected to prove that periodontitis was the main cause of atherosclerosis. It was supposed to increase awareness of periodontitis as a risk and a predisposing factor for atherosclerosis. Although this issue had not been clinically proven, but in my opinion it was important to reduce any oral-origin infection as our effort to maintain healthy mouth and reduce the risk factors for atherosclerosis, otherwise we might miss a chance to help our patients suffering from cardiovascular disease. references 1. Neyer JR, Greenlund KJ, Denny CH, Keenan NL, Labarthe DR, Croft JB. Prevalence of heart disease – united states. CDC 2007; 56(06): 113–8. 143Hudyono and Sunariani: Mechanisms of periodontitis-induced 2. Gaziano JM. Fundamentals of cardiovascular disease. In: Libby P, Bonow RO, Mann DL, Zipes DP. Braunwald�s heart disease: A textbook of cardiovascular medicine. 8th ed. USA: Saunders; 2008. p. 1–21. 3. Vasan RS, Benjamin EJ, Sullivan LM, D�Agostino RB. The burden of increasing worldwide cardiovascular disease. In: Fuster V, Alexander RW, O�Rourke RA. Hurst�s the heart. 11th ed. New York: McGraw- Hill Med Publ; 2004. p. 15–6. 4. World Health Organization. The World Health Report 2002: Reducing risks, promoting healthy life. Geneva: WHO; 2002. 5. Bonow RO, Smaha LA, Smith SC. World Heart Day 2002: The International Burden of cardiovascular disease: responding to the emerging global epidemic. Circulation 2002; 106(13): 1602–5. 6. American Heart Association. Cardiovascular Disease Statistics. Accessed from http://www.americanheart.org on May 5th, 2010. 7. Kristensen PL, Wedderkopp N, Møller NC, Andersen LB, Bai CN, Froberg K. Tracking and prevalence of cardiovascular disease risk factors across socio-economic classes: A longitudinal substudy of the European Youth Heart Study. BMC Public Health 2006; 6:20 Accessed from http://www.biomedcentral.com/1471-2458/6/20 on May 5th, 2010. 8. Libby P. The vascular biology of atherosclerosis. In: Libby P, Bonow RO, Mann DL, Zipes DP. Braunwald�s heart disease: A textbook of cardiovascular medicine. 8th ed. USA: Saunders; 2008. p. 985–1002. 9. Falk E, Shah PK, Fuster V. Atherothrombosis and thrombosis-prone plaques. In: Fuster V, Alexander RW, O�Rourke RA. Hurst�s the heart. 11th ed. New York: McGraw-Hill Med Publ; 2004. p. 1123–40. 10. Epstein SE, Zhou YF, Zhu J. Infection and atherosclerosis emerging mechanistic paradigms. J of Am Heart Assc Circulation 1999; 100: e20–e28. 11. Shoenfeld Y, Gerli R, Doria A, Matsuura E, Cerinic MM, Ronda N, Jara LJ, Abu-Shakra M, Meroni PL, dan Sherer Y. Accelerated atherosclerosis in autoimmune rheumatic diseases. Circulation 2005; 112: 3337–47. 12. Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhollenzer F, Muggeo M, Xu Q, Wick G, Poewe W, Willeit J. Chronic infections and the risk of carotid atherosclerosis: prospective results from a large population study. Circulation 2001; 103: 1064–70. 13. DeStefano F, Anda RF, Kahn HS, Williamson DF, Russell CM. Dental disease and risk of coronary heart disease and mortality. BMJ 1993; 306: 688–91. 14. Mattila KJ, Nieminen MS, Valtonen VV, Rasi VP, Kesäniemi YA, Syrjälä SL, Jungell PS, Isoluoma M, Hietaniemi K, Jokinen MJ. Association between dental health and acute myocardial infarction. BMJ 1989; 298: 779–81. 15. Stein JM, Kuch B, Conrads G, Fickl S, Chrobot J, Schulz S, Ocklenburg C, Smeets R. Clinical periodontal and microbiologic parameters in patients with acute myocardial infarction. J Periodontol. 2009; 80(10): 1581–9. 16. Paul A, Ko KWS, Li L, Yechoor V, McCrory MA, Szalai AJ, Chan L. C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E–Deficient Mice. Circulation 2004; 109: 647–55. 17. Prasad A, Zhu J, Halcox JPJ, Waclawiw MA, Epstein SE, Quyyumi AA. Predisposition to Atherosclerosis by Infections: Role of Endothelial Dysfunction. Circulation 2002; 106: 184–90. 18. Klein EC, Rupprecht HJ, Blankenberg S, Bickel C, Kopp H, Rippin G, Victor A, Hafner G, Schlumberger W, Meyer J. Impact of infectious burden on extent and long-term prognosis of atherosclerosis. Circulation 2002; 105: 15–21. 19. Tzoulaki I, Murray GD, Lee AJ, Rumley A, Lowe GD, Fowkes GR. C-reactive protein, interleukin-6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the general population: edinburgh artery study. Circulation 2005; 112: 976–83. 20. Fruchart JC, Nierman MC, Stroes ESG, Kastelein JJP, Duriez P. New risk factors for atherosclerosis and patient risk assessment. Circulation 2004; 109: III-15-III-19. 21. Dietrich T, Jimenez M, Kaye EAK, Vokonas PS, Garcia RI. Age- dependent associations between chronic periodontitis/edentulism and risk of coronary heart disease. Circulation 2008; 117: 1668–74. 22. Beck JD, Garcia R, Heiss G, Vokonas PS, Offenbacher S. Periodontal disease and cardiovascular disease. J Periodontol. 1996; 67(10 Suppl): 1123–37. 23. Beck JD, Offenbacher S. Relationships among clinical measures of periodontal disease and their associations with systemic markers. Ann Periodontol. 2002 Dec; 7(1): 79–89. 24. Beck JD, Pankow J, Tyroler HA, Offenbacher S. Dental infections and atherosclerosis. Am Heart J. 1999; 138(5 Pt 2): S528–33. 25. Mattila KJ, Asikainen S, Wolf J, Jousimies-Somer H, Valtonen V, Nieminen M. Age, dental infections, and coronary heart disease. Journal of Dental Research 2000; 79(2): 756–60. 26. Gibson, III FC, Hong C, Chou HH, Yumoto H, Chen J, Lien E, Wong J, Genco CA. Innate immune recognition of invasive bacteria accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation 2004; 109: 2801–6. 27. Humagain M, Nayak DG, Uppoor AS. Periodontal infections and cardiovascular disease: Is it a mere association? Kathmandu University Medical Journal 2006: 4(3): 379–82. 28. Friedewald VE, Kornman KS, Beck JD, Genco R, Goldfine A, Libby P, Offenbacher S, Ridker PM, Van Dyke TE Roberts WC. The American Journal of Cardiology and Journal of Periodontology Editors' Consensus: periodontitis and atherosclerotic cardiovascular disease. Journal of Periodontology and The American Journal of Cardiology 2009. 29. Pitiphat W, Savetsilp W, Wara-Aswapati N. C-reactive protein associated with periodontitis in a Thai population. J Clin Periodontol. 2008; 35(2): 120–5. 30. Noack B, Genco RJ, Trevisan M, Grossi S, Zambon JJ, De Nardin E. Periodontal infections contribute to elevated systemic C-reactive protein level. J Periodontol. 2001; 72(9): 1221–7. 31. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation 1998; 97: 425–8. 32. Schillinger M, Exner M, Mlekusch W, Sabeti S, Amighi J, Nikowitsch R, Timmel E, Kickinger B, Minar C, Pones M, Lalouschek W, Rumpold H, Maurer G, Wagner O, Minar E. Inflammation and carotid artery—risk for atherosclerosis study (ICARAS). Circulation 2005; 111: 2203–9. 33. Hommels MJ, van der Ven AJ, Kroon AA, Kessels AG, van Dieijen- Visser MP, van Engelshoven JA, Bruggeman CA, de Leeuw PW. C-reactive protein, atherosclerosis and kidney function in hypertensive patients. Journal of Human Hypertension 2005; 19: 521–6. 34. Schillinger M, Exner M, Amighi J, Mlekusch W, Sabeti S, Rumpold H, Wagner O, Minar E. Joint effects of C-reactive protein and glycated hemoglobin in predicting future cardiovascular events of patients with advanced atherosclerosis. Circulation 2003; 108: 2323–8. 35. Venugopal SK, Devaraj S, Jialal I. C-reactive protein decreases prostacyclin release from human aortic endothelial cells. Circulation 2003; 108: 1676–8. 36. Pasceri V, Willerson JT, dan Yeh ETH. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 2000; 102: 2165–8. 37. Messer JV. C-reactive protein and cardiovascular disease. Circulation 2006; 114: e253–e254. 38. Khera A, de Lemos JA, Peshock RM, Lo HS, Stanek HG, Murphy SA, Wians FH, Grundy SM, McGuire DK. Relationship between C-reactive protein and subclinical atherosclerosis. The Dallas Heart Study. Circulation 2006; 113: 38–43. 39. Haynes WG, Stanford C. Periodontal disease and atherosclerosis: from dental to arterial plaque. Arterioscler Thromb Vasc Biol 2003; 23: 1309–11. 40. Ishihara K, Nabuchi A, Ito R, Miyachi K, Kuramitsu HK, Okuda K. Correlation between detection rates of periodontopathic bacterial DNA in carotid coronary stenotic artery plaque and in dental plaque samples. Journal of Clin Microbiology 2004; 42(3): 1313–5. 41. Mueller HP. Periodontology the essentials. Germany: Georg Thieme Verlag; 2005. p. 31–6, 56. 42. Vernino AR. Etiology of periodontal disease. In: Vernino AR, Gray J, Hughes E. The periodontic syllabus. 5th ed. Philadelphia: Lippincott Williams and Wilkins; 2008. p. 15–25. 144 Indonesian Journal of Tropical and Infectious Disease, Vol. 1. No. 3 September–December 2010: 138-145 43. Taggart EJ, Perry DA in Perry DA, Beemsterboer PL. Periodontology for the dental hygienist. 3rd ed. Missouri: Elsevier Pub; 2007. p. 124–53. 44. Novak MJ. Classification of diseases and conditions affecting the periodontium. In: Newman MG, Takei HH, Klokkevold PR, Carranza FA. Clinical periodontology. 10th ed. St. Louis: Saunders; 2006. p. 100–9. 45. Torrungruang K, Bandhaya P, Likittanasombat K, Grittayaphong C. Relationship between the presence of certain bacterial pathogens and periodontal status of urban Thai adults. J Periodontol. 2009; 80(1): 122–9. 46. Yano-Higuchi K, Takamatsu N, He T, Umeda M, Ishikawa I. Prevalence of Bacteroides forsythus, Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans in subgingival microflora of Japanese patients with adult and rapidly progressive periodontitis. J Clin Periodontol. 2000; 27(8): 597–602. 47. Shah HN, Gharbia SE. Progress in the identification of nonmotile bacteroidaceae from dental plaque. Clin Infectious Disease 1994; 18(Suppl 4): S287–92. 48. Brunner J, Scheres N, El Idrissi NB, Deng DM, Laine ML, van Winkelhoff AJ, Crielaard W. The Capsule of Porphyromonas gingivalis reduces immune response of human gingival fibroblast. BMC Microbiology 2010;10(5). Available at: fromfrom http://www. biomedcentral. com/1471-2180/10/5. 49. Nelson KE, Fleischmann RD, DeBoy RT, Paulsen IT, Fouts DE, Eisen JA, Daugherty SC, Dodson RJ, Durkin AS, Gwinn M, Haft DH, Kolonay JF, Nelson WC, Mason T, Tallon L, Gray J, Granger D, Tettelin H, Dong H, Galvin JL, Duncan MJ, Dewhirst FE, Fraser CM. Complete genome sequence of the oral pathogenic bacterium Porphyromonas gingivalis strain W83. J Bacteriol. 2003; 185(18): 5591–601. 50. Holt SC, Kesavalu L, Walker S, Genco CA. Virulence factors of Porphyromonas gingivalis. Periodontol 2000; 20: 168–238. 51. Sojar HT, Sharma A, dan Genco RJ. Porphyromonas gingivalis fimbriae bind to cytokeratin of epithelial cells. Infection and Immunity 2002; 70(1): 96–101. 52. Graves DT, Naguib G, Lu H, Desta T, Amar S. Porphyromonas gingivalis fimbriae are pro-inflammatory but do not play a prominent role in the innate immune response to P. gingivalis. Journal of Endotoxin Research. 2005; 11(1): 13–8. 53. Quirynen M, Teughels W, Haake SK, Newman MG. Microbiology in periodontal diseases. In: Newman MG, Takei HH, Klokkevold PR, Carranza FA. Clinical periodontology. 10th ed. St. Louis: Saunders; 2006; p. 134–69. 54. Tanamoto K, Azumi S, Haishima Y, Kumada H, Umemoto T. Endotoxic properties of free lipid A from Porphyromonas gingivalis. Microbiology. 1997; 143: 63–71. 55. Andrian E, Grenier D, Rouabhia M. Porphyromonas gingivalis- epithelial cell interactions in periodontitis. J of Dental Research. 2006; 85(5): 392–403. 56. Fox SI. Human physiology. 8th ed. New York: McGraw-Hill Comp; 2004. p. 364–403. 57. Shier D. Hole�s human anatomy and physiology. 9th ed. New York: McGraw-Hill Med Publ; 2002. p. 608–11. 58. Griendling KK, Harrison DG, Alexander RW. Biology of the Vessel Wall. In: Fuster V, Alexander RW, O�Rourke RA. Hurst�s The Heart. 11th Ed. New York: McGraw-Hill Med Publ. 2004; pp. 135–54. 59. Hajjar KA. The Endothelium in Thrombosis and Hemorrhage. In: Loscalzo J, Schafer AI eds. Thrombosis and Hemorrhage. 3rd Ed. Philadelphia: Lippincott Williams & Wilkins. 2003; pp. 207–19. 60. Gokce N, Vita JA. Clinical Manifestations of Endothelial Dysfunction. In: Loscalzo J, Schafer AI eds. Thrombosis and Hemorrhage. 3rd Ed. Philadelphia: Lippincott Williams & Wilkins. 2003; pp. 685–701. 61. Konkle BA, Simon D, Schafer AI. Hemostasis, Thrombosis, Fibrinolysis, and Cardiovascular Disease. In Libby P, Bonow RO, Mann DL, Zipes DP. Braunwald�s Heart Disease A Textbook of Cardiovascular Medicine 8th Ed. USA: Saunders 2008; pp. 2049–75. 62. Davignon J, Ganz P. Role of Endothelial Dysfunction in Atherosclerosis. Circulation 2004; 109: III-27–III-32. 63. Antoniades C, Shirodaria C, Crabtree M, Rinze R, Alp N, Cunnington C, Diesch J, Tousoulis D, Stefanadis C, Leeson P, Ratnatunga C, Pillai R, Channon KM. Altered Plasma Versus Vascular Biopterins in Human Atherosclerosis Reveal Relationships Between Endothelial Nitric Oxide Synthase Coupling, Endothelial Function, and Inflammation. Circulation 2007; 116: 2851–9. 64. Johns DG, Cohen RA. Endothelium-Derived Vasoactive Factors. In: Loscalzo J, Schafer AI eds. Thrombosis and Hemorrhage. 3rd Ed. Philadelphia: Lippincott Williams & Wilkins. 2003; pp. 278–93. 65. Rensen SSM, Doevendans PA, dan van Eys GJ. Regulation and characteristics of vascular smooth muscle cell phenotypic diversity. Neth Heart J. 2007; 15(3): 100–8. 66. Blood Vessels. In: Kumar V, Abbas AK, Fausto N. Robins and Cotran Pathologic Basis of Disease. 7th Ed. Philadelphia: Saunders. 2005; pp. 512–24. 67. Leary MC, Caplan LR. Cerebrovascular Disease and Neurologic Manifestations of Heart Disease. In: Fuster V, Alexander RW, O�Rourke RA. Hurst�s The Heart. 11th Ed. New York: McGraw-Hill Med Publ. 2004; pp. 2333–7. 68. Ikonomidis I, Andreotti F, Economou E, Stefanadis C, Toutouzas P, dan Nihoyannopoulos P. Increased Proinflammatory Cytokines in Patients With Chronic Stable Angina and Their Reduction By Aspirin. Circulation 1999; 100: 793–798. 69. Papapanou PN. Periodontal diseases: epidemiology.Papapanou PN. Periodontal diseases: epidemiology. Periodontal diseases: epidemiology. Ann Periodontol. 1996 Nov; 1(1): 1–36. 70. Irfan UM, Dawson DV, Bissada NF. Epidemiology of periodontal disease: a review and clinical perspectives. J Int Acad Periodontol. 2001; 3(1): 14–21. 71. Demmer RT, Desvarieux M. Periodontal Infections and Cardiovascular Disease: The heart of the matter. J Am Dent Assoc 2006; 137: 14S–20S. 72. Research, Science and Therapy Committee of the American Academy of Periodontology. Epidemiology of Periodontal Diseases. J Periodontol 2005; 76: 1406–1419. 73. Geerts SO, Nys M, De MP, Charpentier J, Albert A, Legrand V, Rompen EH. Systemic release of endotoxins induced by gentle mastication: association with periodontitis severity. J Periodontol. 2002; 73(1): 73–8. 74. Parahitiyawa NB, Jin LJ, Leung WK, Yam WC, dan Samaranayake LP. Microbiology of Odontogenic Bacteremia: beyond Endocarditis. Clin Microbiology Review 2009; 22(1): 46–64 75. Brodala N, Merricks EP, Bellinger DA, Damrongsri D, Offenbacher S, Beck J, Madianos P, Sotres D, Chang YL, Koch G, Nichols TC. Porphyromonas gingivalis Bacteremia Induces Coronary and Aortic Atherosclerosis in Normocholesterolemic and Hypercholesterolemic Pigs. Arterioscler Thromb Vasc Biol. 2005; 25: 1446–1451. 76. Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ: Identification of periodontal pathogens in atheromatous plaques. J Periodontol 2000, 71(10): 1554–1560. 77. Chiu B. Multiple infections in carotid atherosclerotic plaque. Am Heart J. 1999; 138: S534–S536. 78. Grenier D, Tanabe S. Porphyromonas gingivalis Gingipains Trigger a Proinflammatory Response in Human Monocyte-derived Macrophages Through the p38a Mitogen-activated Protein Kinase Signal Transduction Pathway. Toxins 2010; 2(3): 341–352. 79. Hajishengallis G, Wang M, Harokopakis E, Triantafilou M,d dan Triantafilou K. Porphyromonas gingivalis Fimbriae Proactively Modulate _2 Integrin Adhesive Activity and Promote Binding to and Internalization by Macrophages. Infection and Immunity. 2006; 74(10): 5658–66. 80. Ozaki K, Hanazawa S. Porphyromonas gingivalis Fimbriae Inhibit Caspase-3-Mediated Apoptosis of Monocytic THP-1 Cells under Growth Factor Deprivation via Extracellular Signal-Regulated Kinase-Dependent Expression of p21 Cip/WAF1. Infection and Immunity. 2001; 69(8): 4944–50. 81. Wang M, Shakhatreh MA, James D, Liang S, Nishiyama S, Yoshimura F, Demuth DR, dan Hajishengallis G. Fimbrial Proteins of Porphyromonas and Exploit TLR2 and Complement gingivalis Mediate In Vivo Virulence Receptor 3 to Persist in Macrophages. J. Immunol. 2007; 179: 2349–58. 82. Li L, Michel R, Cohen J, DeCarlo A, dan Kozarov E. Intracellular survival and vascular cell-to-cell transmission of Porphyromonas gingivalis. BMC Microbiology 2008; 8: 26. Downloaded from: http://www.biomedcentral.com/1471-2180/8/26. 145Hudyono and Sunariani: Mechanisms of periodontitis-induced 83. Ho YS, Lai MT, Liu SJ, Lin CT, Naruishi K, Takashiba S, Chou HH. Porphyromonas gingivalis fimbriae-dependent interleukin-6 autocrine regulation by increase of gp130 in endothelial cells. J Periodontal Res. 2009; 44(4): 550–6. 84. Chou HH, Yumoto H, Davey M, Takahashi Y, Miyamoto T, Gibson III FC, dan Genco CA. Porphyromonas gingivalis Fimbria-Dependent Activation of Inflammatory Genes in Human Aortic Endothelial Cells. Infection and Immunity 2005; 73(9): 5367–78. 85. Davey M , Liu X, Ukai T, Jain V, Gudino C, Gibson III FC, Golenbock D, Visintin A, dan Genco CA. Bacterial Fimbriae Stimulate Proinflammatory Activation in the Endothelium through Distinct TLRs. The Journal of Immunology 2008; 180: 2187–95 86. Jotwani R, Cutler CW. Fimbriated Porphyromonas gingivalis Is More Efficient than Fimbria-Deficient P. gingivalis in Entering Human Dendritic Cells In Vitro and Induces an Inflammatory Th1 Effector Response. Infection and Immunity. 2004; 72(3): 1725–32. 87. Kleemann R, Zadelaar S, dan Kooistra T. Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovascular Research 2008; 79: 360–76. 88. Zhang D, Chen L, Li S, Gu Z, dan Yan J. Lipopolysaccharide (LPS) ofLipopolysaccharide (LPS) of Porphyromonas gingivalis induces IL-1b, TNF-a and IL-6 production by THP-1 cells in a way different from that of Escherichia coli LPS. Innate Immunity. 2008; 14(2): 99–107. 89. Yang RB, Mark MR, Gurney AL, dan Godowski PJ. Signaling Events Induced by Lipopolysaccharide-Activated Toll-Like Receptor 2. The Journal of Immunology. 1999; 163: 639–643. 90. Burns E, Eliyahu T, Uematsu S, Akira S, dan Nussbaum G. TLR2- Dependent Inflammatory Response to Porphyromonas gingivalis Is MyD88 Independent, whereas MyD88 is Required to Clear Infection. The Journal of Immunology, 2010, 184, 1455–1462. 91. Hajishengallis G, Sojar. H, Genco RJ, dan DeNardin E. Intracellular Signaling and Cytokine Induction upon Interactions of Porphyromonas gingivalis Fimbriae with Pattern-Recognition Receptors. Immunological Investigations 2004; 33(2): 157–172. 92. Beck JD, Elter JR, Heiss G, Couper D, Mauriello SM, Offenbacher S. Relationship of Periodontal Disease to Carotid Artery Intima-Media Wall Thickness The Atherosclerosis Risk in Communities (ARIC) Study Arteriosclerosis, Thrombosis, and Vascular Biology. 2001; 21: 1816. 93. Abbas A, Lichtman AH, Pober JS. Cellular and Molecular Immunology. 3rd Ed. USA: WB Saunders Comp. 1997; pp. 250–76. 94. Zhang L, Peppel K, Brian L, Chien L, Freedman NJ. Vein graft neointimal hyperplasia is exacerbated by tumor necrosis factor receptor-1 signaling in graft-intrinsic cells. Arterioscler Thromb Vasc Biol. 2004; 24(12): 2277–83. 95. Paoletti R, Gotto AM, Hajjar DP. Inflammation in Atherosclerosis and Implications for Therapy. Circulation 2004; 109: III-20–III-26 96. Chan J, Lourenco LP, Khachigian LM, Bennett MR, DiBartolo BA, Kavurma MM. TRAIL Promotes VSMC Proliferation and Neointima Formation in a FGF-2–, Sp1 Phosphorylation–, and NFkB-Dependent Manner. Circulation Research. 2010; 106: 1061. 97. Plümpe J, Malek NP, Bock CT, Rakemann T, Manns MP, dan Trautwein C. NF-kB determines between apoptosis and proliferation in hepatocytes during liver regeneration. Am J Physiol Gastrointest Liver Physiol 2000; 278: G173–G183. 98. Bellas RE, FitzGerald MJ, Fausto N, dan Sonenshein GE. Inhibition of NF-kB activity induces apoptosis in murine hepatocytes. American Journal of Pathology 1997; 151: 891–896. 99. Ryan KM, Ernst MK, Rice NR, dan Vousden KH. Role of NF-kB in p53-mediated programmed cell death. Nature 2000; 404: 892–897. 100. Schwarz EM, Badorff C, Hiura TS, Wessely R, Badorff A, Verma IM, dan Knowlton KU. NF-kB-Mediated Inhibition of Apoptosis Is Required for Encephalomyocarditis Virus Virulence: a Mechanism of Resistance in p50 Knockout Mice. J Virol 1998; 72(7): 5654–5660. 101. Cobb JP, Hotchkiss RS, Karl IE, dan Buchman TG. Mechanisms of Cell Injury and Death. Brit J of Anaest. 1996; 77: 3–10 102. Kovacs A, Weber ML, Burns LJ, Jacob HS, Vercellotti GM. Cytoplasmic sequestration of p53 in cytomegalovirus-infected human endothelial cells. Am J Pathol. 1996; 149: 1531–1539. 103. Clinton SK, Underwood R, Hayes L, Sherman ML, Kufe DW, Libby P. Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis. Am J Pathol. 1992; 140(2): 301–16. 104. Eubank TD, Galloway M, Montague CM, Waldman WJ, dan Marsh CB. M-CSF Induces Vascular Endothelial Growth Factor Production and Angiogenic Activity From Human Monocytes. The Journal of Immunology 2003; 171: 2637–43. 105. Kaushansky K, Lin N, Adamson JW. Interleukin-1 Stimulates Fibroblasts to Synthesize Granulocyte-Macrophage and Granulocyte- Colony Stimulating Factors. J Clin Invest. 1988; 81: 92–7. 106. Chi H, Messas E, Levine RA, Graves DT and Amar S. Interleukin- 1 Receptor Signaling Mediates Atherosclerosis Associated With Bacterial Exposure and/or a High-Fat Diet in a Murine Apolipoprotein E Heterozygote Model: Pharmacotherapeutic Implications. Circulation 2004; 110: 1678–168. 107. Kleenmann R, Zadelaar S, Kooistra T. Cytokines and Atherosclerosis: a comprehensive review of studies in mice. Cardiovascular Research 2008; 79: 360–76. 108. Henninger DD, Panes J, Eppihimer M, Russell J, Gerritsen M, Anderson DC, dan Granger DN. Cytokine-induced VCAM-1 and ICAM-1 expression in different organs of the mouse. J of Immunology 1997; 158(4): 1825–1832. 109. Ley K, dan Huo Y. VCAM-1 is Critical in Atherosclerosis. J. Clin. Invest. 2001; 107(10): 1209–10. 110. Lawson C, Ainsworth M, Yacoub M, dan Rose M. Ligation of ICAM- 1 on Endothelial Cells Leads to Expression of VCAM-1 Via a Nuclear Factor-kB-Independent Mechanism. The Journal of Immunology 1999; 162: 2990–6. 111. Pasceri V, Chang J, Willerson JT dan Yeh ETH. Modulation of C-Reactive Protein–Mediated Monocyte Chemoattractant Protein-1 Induction in Human Endothelial Cells by Anti-Atherosclerosis Drugs. Circulation 2001; 103: 2531–4. 112. Liao F, Andalibi A, Lusis AJ, Fogelman AM. Genetic control of the inflammatory response induced by oxidized lipids. Am J Cardiol. 1995; 75: 65B–66B. 113. Liao F, Rabin RL, Yannelli JR, Koniaris LG, Vanguri P, Farber JM: Human MIG chemokine: Biochemical and functional characterization. J Exp Med 182: 1301–1314, 1995. 114. Lee SK, Kim JH, Yang WS, Kim SB, Park SK, Park JS. Exogenous Nitric Oxide Inhibits VCAM-1 Expression in Human Peritoneal Mesothelial Cells Role of Cyclic GMP and NF-kB. Nephron 2002; 90: 447–454. 115. Kawachi S, Cockrell A, Laroux FS, Gray L, Granger DN, van der Heyde HC, dan Grisham MB. Role of inducible nitric oxide synthase in the regulation of VCAM-1 expression in gut inflammation. Am J Physiol Gastrointest Liver Physiol 1999; 277: G572–G576. 116. Khan BV, Harrison DG, Olbrych MT, Alexander W, dan Medford RM. Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proc. Natl. Acad. Sci. USA 1996; 93: 9114–9. 117. Hemodynamic disorders, thromboembolic disease, and shock. In: Kumar V, Abbas AK, Fausto N. Robins and cotran pathologic basis of disease. 7th ed. Philadelphia: Saunders 2005; pp. 124–35 118. Hua Cai, David G. Harrison endothelial dysfunction in cardiovascular diseases: The role of oxidant stress. Circulation Research. 2000; 87: 840. 119. Zhang P, Hou M, Li Y, Xu X, Barsoum M, Chen YJ, Bache RJ. NADPH oxidase contributes to coronary endothelial dysfunction in the failing heart. Am J Physiol Heart Circ Physiol 2009; 296: H840–H846. 120. Hajjar DP, Falcones DJ, Fabricant CG, Fabricant J. Altered cholesteryl ester cycle is associated with lipid accumulation in herpesvirus- infected arterial smooth muscle cells. J of Biological Chemistry. 1985; 260(10): 6124–8. 121. Hajjar DP, Pomerantz KB, Falcone DJ, Weksler BB, Grant AJ. Herpes simplex virus infection in human arterial cells. Implications in arteriosclerosis. J. Clin. Invest. 1987; 80(5): 1317–21. 122. de Villiers WJ, Smart EJ. Macrophage scavenger receptors and foam cell formation. Journal of Leukocyte Biology 1999; 66(5): 740–6. 123. Zhao Z, de Beer MC, Cai L, Asmis R, de Beer FC, de Villiers WJS, van der Westhuyzen WR. Low-Density Lipoprotein From Apolipoprotein E-Deficient Mice Induces Macrophage Lipid Accumulation in a CD36 and Scavenger Receptor Class A-Dependent Manner. Shouxi 2006; 10:26. Downloaded from http://journal.shouxi.net/qikan/article. php?id=201401. IJTID vol 1 no 3 Sep-Dec 2010.36.pdf IJTID vol 1 no 3 Sep-Dec 2010.37.pdf IJTID vol 1 no 3 Sep-Dec 2010.38.pdf IJTID vol 1 no 3 Sep-Dec 2010.39.pdf IJTID vol 1 no 3 Sep-Dec 2010.40.pdf IJTID vol 1 no 3 Sep-Dec 2010.41.pdf IJTID vol 1 no 3 Sep-Dec 2010.42.pdf IJTID vol 1 no 3 Sep-Dec 2010.43.pdf