穿心蓮在傳統醫學上常用於治療感冒，因此評估穿心蓮萃取物是否具有毒性 值得注意。急性口服毒性數據測試可用來評估人類在使用藥物上的風險。
Chandrasekaran 等人(2009)以 8-12 週的大鼠來做急性口服毒性試驗，研究發現每
公斤體重的大鼠給予穿心蓮萃出物5000 mg，研究結束大鼠仍存活，並在 14 天的
實驗期間，並沒有顯示出任何的不良症狀，也沒有任何不正常的體重增加情形。
但是，有文獻指出，每天給予雄性小白鼠乾燥的穿心蓮葉磨成的粉末20 mg，持
續 60 天會停止精子的產生(Akbarsha et al., 1990)。廣州中醫藥大學徐等人(2005)，
以小鼠來做急性毒性試驗，每公斤體重管灌穿心蓮軟膠囊內容物15 ml(每粒膠囊
含有2.1 g 的穿心蓮生藥)，一天兩次，一日總給藥量為 110.25 g/kg，並連續觀察 14 天，結果發現給藥後的小鼠無躁動不安、呼吸困難、突眼等急性毒性表現，給
藥後連續觀察14 天並無小鼠死亡，且藥後兩周內小鼠的正常生長週期並未顯著
受影響，此急性毒性試驗發現，小鼠一日最大耐受量為110.25 g/kg，相當於成人
臨床推薦用量的525 倍，顯示穿心蓮在臨床上的應用是安全的。此外，在中草藥
被廣泛應用的現代社會，中草藥與藥物間的交互作用也是一個嚴重的問題，以動
物模式利用HPLC/UV 來分析穿心蓮萃出物的成分，實驗發現預先給予穿心蓮內
酯可以增加血液內茶鹼(theophylline)的清除，若長期使用穿心蓮則會提高茶鹼在
血液內的濃度，研究中提出穿心蓮萃出物和其中的草藥成分會和CYP1A2 產生交
互作用，因此在使用上應多加留意(Chien et al., 2010)。
研究目的
動脈粥狀硬化是一種慢性發炎疾病，會造成血管內壁脂肪堆積及纖維斑塊形 成，是導致心血管疾病的主要原因之一。許多文獻指出穿心蓮及穿心蓮內酯皆具 有抗發炎的藥理作用，而穿心蓮內酯更是穿心蓮中的重要活性成分，因此本實驗 將利用內皮細胞株EA. hy926 以腫瘤壞死因子 TNF-α 誘發其發炎反應，之後探討 穿心蓮內酯對於內皮細胞發炎反應的影響及其作用機制。
文獻參考
徐志勇.(2005). 穿心蓮軟膠囊與穿心蓮片的藥理作用及急性毒性實驗研究. 廣州中 醫藥大學.
Arjan van der Flier, Arnoud Sonnenberg.(2001). Function and interactions of integrins.
Cell Tissue Res 305, 285–298.
Akihiro Yachie, Yo Niida, Taizo Wada, Noboru Igarashi, Hisashi Kaneda, Tomoko Toma, Kazuhide Ohta, Yoshihito Kasahara and Shoichi Koizumi. (1999). Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. European Journal of Clinical Investigation. 103, 129-135.
Akbarsha, M.A., Manivannan, B., Hamid, K.S., Vijayan, B., (1990). Antifertility effect of Andrographis paniculata (Nees) in male albino rat. Indian Journal of Experimental
Biology. 28, 421–426.
By Sophie Brouard, Leo E. Otterbein, Josef Anrather, Edda Tobiasch, Fritz H. Bach, Augustine M.K. Choi, and Miguel P. Soares. (2000). Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. The Journal of Experimental Medicine. 192,1015–1026
Baranano, D. E., Rao, M., Ferris, C. D. and Snyder, S. H. (2002). Biliverdin reductase: a major physiologic cytoprotectant. Proceedings of the National Academy of Sciences of the United States of America 99, 16093-16098.
Briscoe DM, Cotran RS, Pober JS. (1992) Effects of tumor necrosis factor,
lipopolysaccharide, and IL-4 on the expression of vascular cell adhesion molecule 1 in vivo: correlation with CD3+ T-cell infiltration. Journal of Immunology. 149, 2954–2960.
Claudio fiocchi (1998). Inflammatory Bowel Disease: Etiology and Pathogenesis.
Gastroenterology. 115, 182–205.
Chiou,W. F., Chen, C. F. and Lin, J. J. (2000). Mechanisms of suppression of inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells by andrographolide. British Journal of Pharmacology. 129, 1553–1560.
Chao-Feng Chiena, Yu-Tse Wua, Wen-Chuan Leea, Lie-Chwen Linb, Tung-Hu Tsai.
(2010). Herb–drug interaction of Andrographis paniculata extract and andrographolide on the pharmacokinetics of theophylline in rats. Chemico-Biological Interactions. 184, 458–465.
C.V. Chandrasekaran , P. Thiyagarajan, K. Sundarajan, Krishna S. Goudar, M. Deepak, B. Murali, J. Joshua Allan, Amit Agarwal.(2009). Evaluation of the genotoxic potential and acute oral toxicity of standardized extract of Andrographis paniculata (KalmColdTM).
Food and Chemical Toxicology. 47, 1892–1902.
D. Zapolska-Downar, A. Zapolski-Downar , M. Markiewski , A. Ciechanowicz , M.
Kaczmarczyk , M. Naruszewicz. (2001). Selective inhibition by probucol of vascular cell adhesion molecule-1 (VCAM-1) expression in human vascular endothelial cells.
Atherosclerosis. 155,123–130.
Eriksson EE, Xie X, Werr J, Thoren P, Lindbom L.(2001) Importance of primary capture and L-selectin-dependent secondary capture in leukocyte accumulation in inflammation and atherosclerosis in vivo. The Journal of Experimental Medicine. 194, 205–218.
Fondevila, C., Shen, X. D., Tsuchiyashi, S., Yamashita, K.,Csizmadia, E.,Lassman, C., Busuttil, R. W., Kupiec-Weglinski, J. W. and Bach, F. H. (2004). Biliverdin therapy protects rat livers from ischemia and reperfusion injury. Hepatology. 40, 1333-1341.
Grosser, N., Oberle, S., Berndt, G., Erdmann, K., Hemmerle, A. and Schroder, H.(2004).
Antioxidant action of L-alanine: heme oxygenase-1 and ferritin as possible mediators.
Biochem. Biophys. Res. Commun. 314, 351-355.
Gonzales, S., Polizio, A. H., Erario, M. A. and Tomaro, M. L.(2005). Glutamine is highly effective in preventing in vivo cobalt-induced oxidative stress in rat liver. World J.
Gastroenterol. 11, 3533-3538.
Galkina E, Kadl A, Sanders J, Varughese D, Sarembock IJ, Ley K.(2006).Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is
Gunter voraberger, renate schafer, and christian stratowa.(1991).Cloning of the human gene for intercellular adhesion molecule and analysis of its 5”regulatory region Induction by Cytokines and Phorbol Ester.The Journal of Immunology. 147, 2777-2786.
Gahmberg CG, Tolvanen M, Kotovuori P. (1997). Leukocyte adhesion structure and function of human leukocyte beta2-integrins and their cellular ligands. European Journal of Biochemistry/FEBS. 245, 215-232.
Guan JL, Hynes RO.( 1990). Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor alpha 4 beta 1. Cell. 60, 53– 61.
Giovanni E. Mann, Jörg Niehueser-Saran, Alan Watson, Ling Gao, Tetsuro Ishii, Patricia de Winter, Richard C. M. Siow.(2007). Nrf2/ARE regulated antioxidant gene expression in endothelial and smooth muscle cells in oxidative stress: implications for atherosclerosis and preeclampsia. Acta Physiologica Sinica. 59, 117-127.
Gupta, S., Choudhry, M. A., Yadava, J. N. S., Srivastava, V. and Tandon, J. S. (1990).
Antidiarrhoeal activity of diterpenes of Andrographis paniculata (Kal-Megh) against Escherichia coli enterotoxin in in vivo models. International Journal of Crude Drug Research. 28, 273–283.
Huang HC, Nguyen T, Pickett CB. (2002). Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element -mediated transcription. The Journal of
Biological Chemistry.; 277: 42769-42774.
Hidalgo MA, Romero A, Figueroa J, Cortes P, Concha II, Hancke JL, Burgos RA.
(2005). Andrographolide interferes with binding of nuclear factor-kB to DNA in HL-60-derived neutrophilic cells. British Journal of Pharmacology. 144, 680–686.
Hon-Yeung Cheung, Sau-Ha Cheung, Jieliang Li, Chui-Shan Cheung, Wai-Ping Lai, Wang-Fun Fong, Fo-Man Leung.(2005). Andrographolide isolated from Andrographis paniculata induces cell cycle arrest and mitochondrial-mediated apoptosis in human leukemic HL-60 cells. Planta medica. 71, 1106-1111.
Handa, S. and Sharma, A. (1990). Hepatoprotective activity of andrographolide against galactosamine & paracetamol intoxication in rats. The Indian Journal of Medical Research.
92, 284–292.
Immenschuh, S., Schroder, H.(2006). Heme oxygenase-1 and cardiovascular disease.
Histology and histopathology. Cellular and Molecular Biology. 21, 679–685.
Ishikawa, K., Takeuchi, N., Takahashi, S., Matera, K. M., Sato, M., Shibahara, S., Rousseau, D. L., Ikeda-Saito, M. and Yoshida, T. (1995). Heme oxygenase-2. Properties of the heme complex of the purified tryptic fragment of recombinant human heme oxygenase-2. The Journal of Biological Chemistry. 270, 6345-6350.
Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M. (2000). Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. The Journal of Biological Chemistry. 275,
16023-16029.
Iruretagoyena MI, Tobar JA, Gonzalez PA, Sepulveda SE, Figueroa CA, Burgos RA.
(2005). Andrographolide interferes with T Cell activation and reduces experimental autoimmune encephalomyelitis in the mouse. The Journal of Pharmacology and Experimental Therapeutics. 312, 366–372.
Johnson-Tidey RR, McGregor JL, Taylor PR, Poston RN. (1994). Increase in the adhesion molecule P-selectin in endothelium overlying atherosclerotic plaques. Coexpression with intercellular adhesion molecule-1. The American Journal of Pathology. 144, 952–961.
James W. Kaspar, Suryakant K. Niture, Anil K. Jaiswal. (2009). Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radical Biology & Medicine. 47, 1304–1309.
Kanokwan Jarukamjorn, and Nobuo Nemoto. (2008). Pharmacological aspects of Andrographis paniculata on health and its major diterpenoid constituent
Andrographolide.Journal of Health Science. 54, 370–381.
Kumar RA, Sridevi K, Kumar NV, Nanduri S, Rajagopal S. (2004). Anticancer and immunostimulatory compounds from Andrographis paniculata. Journal of
Ethnopharmacology. 92, 291-295.
Kapil, A., Koul, I. B., Banerjee, S. K. and Gupta, B. D. (1993). Antihepatotoxic effects of major diterpenoid constituents of Andrographis paniculata.
Karin, M. (1996). The regulation of AP-1 activity by mitogen-activated protein kinases.
Philosophical transactions of the Royal Society of London. Series B, Biological Sciences.
351, 127–134.
Koichiro Sato, Jozsef Balla, Leo Otterbein, R. Neal Smith, Sophie Brouard, Yuan Lin, Eva Csizmadia, Jean Sevigny, Simon C. Robson, Gregory Vercellotti, Augustine M. Choi, Fritz H. Bach and Miguel P. Soares. (2001). Carbonmonoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants. American Journal of Immunology. 166, 4185–4194.
Kelly J. Peyton, Sylvia V. Reyna, Gary B. Chapman, Diana Ensenat, Xiao-ming Liu, Hong Wang, Andrew I. Schafer, and William Durante.(2002). Heme oxygenase-1-derived carbon monoxide is an autocrine inhibitor of vascular smooth muscle cell growth. Blood . 99, 4443–4448.
L.A. Stanciu, R. Djukanovic (1998). The role of ICAM-1 on T-cells in the pathogenesis of asthma.The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 11, 949–957.
Leo E. Otterbein, Miguel P. Soares, Kenichiro Yamashita and Fritz H. Bach. (2003). Heme oxygenase-1: unleashing the protective properties of heme. Trends in Immunology. 24, 449-455.
Lin-Hua QIN, Ling KONG, Guo-Jun SHI, Zheng-Tao WANG, and Bao-Xue G. (2006).
Andrographolide Inhibits the Production of TNF-α and Interleukin-12 in
Lipopolysaccharide-Stimulated Macrophages: Role of Mitogen-Activated Protein Kinases. Biological & Pharmaceutical Bulletin. 29, 220-224.
Llesuy, S. F and Tomaro, M. L. (1994). Heme oxygenase and oxidative stress. Evidence of involvement of bilirubin as physiological protector against oxidative damage.
Biochimica et Biophysica acta. 1223, 9-14.
Li, J., Cheung, H. Y., Zhang, Z., Chan, G. K. L. and Fong,W. F.(2007). Andrographolide induces cell cycle arrest at G2/M phase and cell death in HepG2 cells via alteration of reactive oxygen species. European Journal of Pharmacology. 568, 31–44.
Look, D. C., Pelletier, M. R., Tidwell, R. M., Roswit, W. T., Holtzman, M. J. (1995).
Stat1 depends on transcriptional synergy with Sp1. The Journal of Biological Chemistry.
270, 30264–30267.
Leo E. Otterbein, Brian S. Zuckerbraun, Manabu Haga, Fang Liu, Ruiping Song, Anny Usheva ,Christina Stachulak, Natalya Bodyak, R. Neal Smith, Eva Csizmadia, Shivraj Tyagi, Yorihiro Akamatsu, Richard J. Flavell, Timothy R. Billiar, Edith Tzeng, Fritz H.
Bach, Augustine M.K. Choi & Miguel P. Soares .(2003). Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury.
Journal of Natural Medicines. 9, 183–190.
Maines, M. D. and Gibbs, P. E. (2005). 30 some years of heme oxygenase: from a
“molecular wrecking ball” to a “mesmerizing” trigger of cellular events. Biochemical and Biophysical Research Communications. 338, 568-577.
Maines, M. D. (1988). Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. The Fede ration of American Societies for Experimental Biology.
2, 2557-2568.
McCoubrey, W. K. Jr., Huang, T. J. and Maines, M. D. (1997). Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. European Journal of Biochemistry/FEBS. 247, 725-732.
Motterlini, R., Foresti, R., Bassi, R., Calabrese, V., Clark, J. E. and Green, C. J. (2000).
Endothelial heme oxygenase-1 induction by hypoxia. Modulation by inducible nitric-oxide synthase and S-nitrosothiols. The Journal of biological chemistry. 275, 13613-13620.
Moore, B. A., Overhaus, M., Whitcomb, J., Ifedigbo, E., Choi, A. M., Otterbein, L. E. and Bauer, A. J. (2005). Brief inhalation of low-dose carbon monoxide protects rodents and swine from postoperative ileus. Critical Care Medicine. 33, 1317-1326.
Malaguarnera, L., Madeddu, R., Palio, E., Arena, N. and Malaguarnera, M. (2005).
Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients . Journal of Hepatology. 42, 585-591.
Menno P.J. de Winther, Edwin Kanters, Georg Kraal, Marten H. Hofker. (2005). Nuclear Factor B Signaling in Atherogenesis. Arteriosclerosis, Thrombosis, and Vascular biology.
25, 904-914.
860–866.
Mahin D Maines.(2001). The heme oxygenase sytem: Update 2005. Antiox Redox Signal.7, 1761-1766.
N. Poolsup PhD, C. Suthisisang PhD, S. Prathanturarug PhD, A. Asawamekin BPharm and U. Chanchareon BPharm.(2004). Andrographis paniculata in the symptomatic treatment of uncomplicated upper respiratory tract infection: systematic review of randomized controlled trials.Journal of Clinical Pharmacy and Therapeutics. 29, 37–45.
Ossola, J. O. and Tomaro, M. L.(1998). Heme oxygenase induction by UVA radiation. A response to oxidative stress in rat liver. The International Journal of Biochemistry & Cell Biology. 30, 285-292.
Pholphana, N., Rangkadilok, N., Thongnest, S., Ruchirawat, S., Ruchirawat, M. and Satayavivad. (2004). Determination and variation of three active diterpenoids in Andrographis paniculata (Burm.f.) Nees. Phytochemical Analysis. 15, 365–371.
Pannen, B. H., Kohler, N., Hole, B., Bauer, M., Clemens, M. G. and Geiger, K. K. (1998).
Protective role of endogenous carbon monoxide in hepatic microcirculatory dysfunction after hemorrhagic shock in rats. European Journal of Clinical Investigation. 102,
1220-1228.
P J Lee, J Alam, G W Wiegand, and A M Choi. (1996). Overexpression of heme oxygenase-1 in human pulmonary epithelial cells results in cell growth arrest and increased resistance to hyperoxia. Proceedings of the National Academy of Sciences of the United States of America. 93, 10393–10398.
Ryter, S.W., Alam, J., Choi, A.M.K. (2006). Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiological Reviews. 86, 583–650.
Ramos CL, Huo Y, Jung U, Ghosh S, Manka DR, Sarembock IJ, Ley K. (1999). Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice. Circulation Research. 84, 1237–1244.
Ross R (1999). Atherosclerosis- an inflammatory disease. The New England journal of medicine. 340(2):115-26.
Sarady, J. K., Zuckerbraun, B. S., Bilban, M., Wagner, O., Usheva, A., Liu, F., Ifedigbo, E., Zamora, R., Choi, A. M. and Otterbein, L.E. (2004). Carbon monoxide protection
against endotoxic shock involves reciprocal effects on iNOS in the lung and liver. The Federation of American Societies for Experimental Biology. 18, 854-856.
Sawle, P., Foresti, R., Mann, B. E., Johnson, T. R., Green, C. J. and Motterlini, R. (2005).
Carbon monoxide-releasing molecules (CO-RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages. British Journal of Pharmacology. 145, 800-810.
Sheeja, K., Shihab, P. K. and Kuttan, G.(2006). Antioxidant and anti-inflammatory activities of the plant Andrographis Paniculata Nees. Immunopharmacology and Immunotoxicology. 28, 129–140.
Singha, P. K.; Roy, S. Dey, S. (2007). Protective activity of andrographolide and arabinogalactan proteins from Andrographis paniculata Nees. against ethanol-induced toxicity in mice. J. Ethnopharmacol. 111, 13–21.
Sheeja K, Guruvayoorappan C, Kuttan G. (2007). Antiangiogenic activity of
Andrographis paniculata extract and andrographolide. International Immunopharmacology.
7, 211–221.
Stefan Blankenberg , Sandrine Barbaux , Laurence Tiret. (2003). Adhesion molecules and atherosclerosis. Atherosclerosis. 170, 191-203.
Song, S., Ling-Hu, H., Roebuck, K. A., Rabbi, M. F., Donnelly, R. P., Finnegan, A.(1997).
Interleukin-10 inhibits interferon-gamma-induced intercellular adhesion molecule-1 gene transcription in human monocytes. Blood. 89, 4461–4469.
Tobiasch, Edda; Günther, Lukas; Bach, Fritz H. (2001). Heme oxygenase-1 protects pancreatic beta cells from apoptosis caused by various stimuli. Investigación Médica Internacional. 49, 566–571.
Trivedi, N. and Rawal, U. M. (2001). Hepatoprotective and antioxidant property of Andrographis paniculata (Nees) in BHC induced liver damage in mice.
Indian Journal of Experimental Biology. 39, 41–46.
Vojdani A, Erde J. (2006) Regulatory T cells, a potent immunoregulatory target for CAM researchers: modulating tumor immunity, autoimmunity
Victor J. Dzau, Ruediger C. Braun-Dullaeus & Daniel G. (2002). Vascular proliferation and atherosclerosis: New perspectives and therapeutic strategies. Nature Medicine. 8, 1249-1256.
Wiart, C., Kumar, K.,Yusof, M. Y., Hamimah, H., Fauzi, Z. M. and Sulaiman, M. (2005).
Antiviral properties of ent-labdene diterpenes of Andrographis paniculata Nees, inhibitors of herpes simplex virus type 1. Phytotherapy Research. 19, 1069-1070.
Wen-Wan Chao, Yueh-Hsiung Kuo, Shie-Liang Hsieh and Bi-Fong Lin. (2009).
Inhibitory effects of ethyl acetate extract of Andrographis paniculata on NF-κB
trans-activation activity and LPS-induced acute inflammation in mice. Evidence-based Complementary and Alternative Medicine. 10, 1-9.
Yuh-Chiang Shen, Chieh-Fu Chen & ,Wen-Fei Chiou. (2002). Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism(s) involved in its anti-infammatory effect. British Journal of Pharmacology. 135, 399-406.
Yi-Chieh Lee , Hui-Hsuan Lin , Chin-Hsun Hsu, Chau-Jong Wang , Tai-An Chiang , Jing-Hsien Chen.(2010). Inhibitory effects of andrographolide on migration and invasion in human non-small cell lung cancer A549 cells via down-regulation of PI3K/Akt
signaling pathway. European Journal of Pharmacology. 632, 23-32.
Yu G, Rux AH, Ma P, Bdeir K, Sachais BS. (2005). Endothelial expression of E-selectin is induced by the platelet-specific chemokine platelet factor 4 through LRP in an
NF-kappaB-dependent manner. Blood. 105, 3545–3551.
Zipper, L. M.; Mulcahy, R. T. (2002). The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm. The Journal of Biological Chemistry.
277, 36544-36552.
Zhou, J., Zhang, S., Ong, C. and Shen, H. (2006). Critical role of pro-apoptotic Bcl-2 family members in andrographolide-induced apoptosis in human cancer cells.
Biochemical Pharmacology. 72, 132-144.
Zhang Bao1, Shouping Guan, Chang Cheng, Songlian Wu, Siew Heng Wong, D. Michael Kemeny, Bernard P. Leung, and W. S. Fred Wong. (2009). A Novel Antiinflammatory Role for Andrographolide in Asthma via Inhibition of the Nuclear Factor-kB Pathway.
American Journal of Respiratory and Critical Care Medicine. 179, 657-665.
第二部分
Induction of Heme Oxygenase 1 and Inhibition of Tumor Necrosis Factor α-Induced Intercellular Adhesion Molecule
Expression by Andrographolide in EA.hy926 Cells
INTRODUCTION
Current epidemiologic predictions suggest that cardiovascular disease (CVD) is reaching pandemic proportions (1), and CVD is the leading cause of death worldwide, accounting for ~16.7 million deaths each year (2). This number is predicted to reach approximately 25 million by 2020, if current trends continue (3). The reasons for the increased global incidence of CVD include the aging of the world’s population and lifestyles in lower- and middle-income countries becoming more akin to those of wealthier nations (1).
CVD is partially characterized by chronic inflammation and an increased level of expression of inflammatory biomarkers, such as intercellular adhesionmolecule
(ICAM-1), vascular cell adhesion molecule (VCAM-1), and E-selectin, on the surface of the activated endothelial cells (EC) and in the blood circulation (4). Increased circulating levels of these adhesion molecules are considered to be predictive of CVD risk because they indicate a proinflammatory state in the vasculature (4). In vivo
inflammatory processes are mediated by the involvement of proinflammatory mediators, including tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-12, and interferon γ
regulate their activation (5). When confronted by an inflammatory stimulus, e.g.,
bacterial lipopolysaccharide (LPS) (6), TNF-α(7), or IL-1β (8), EC become activated as a result of modification of their phenotype. This is accompanied primarily by the
upregulation of a series of proinflammatory genes, e.g., E-selectin, P-selectin, VCAM-1, and ICAM-1 (6-8). The expression of these genes is regulated primarily by the
activation of transcription factor NF-κB (9). The proper production of proinflammatory cytokines aids in innate immune responses; however, overproduction causes undesirable side effects such as tissue injury, septic shock, and even death (10). To avoid the
consequences of uncontrolled production, the expression of proinflammatory genes must be strictly regulated (11). One of the mechanisms by which inflammation is counteracted is the expression of the anti-inflammatory genes of activated EC. Because of their dual ability to inhibit the expression of proinflammatory genes associated with EC activation and to protect EC from undergoing apoptosis, Bach and colleagues (11)
consequences of uncontrolled production, the expression of proinflammatory genes must be strictly regulated (11). One of the mechanisms by which inflammation is counteracted is the expression of the anti-inflammatory genes of activated EC. Because of their dual ability to inhibit the expression of proinflammatory genes associated with EC activation and to protect EC from undergoing apoptosis, Bach and colleagues (11)