丹参酮ⅡA干预趋化因子MCP-1调控心肌梗死后炎症的机制研究
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摘要
缺血性心脏病是严重危害人类健康的疾病之一。丹参酮ⅡA(TanⅡA)是活血化瘀中药丹参的主要脂溶性活性成分之一,近年来已有报道证明TanⅡA对心血管疾病有很好的治疗效果,但其对心肌梗死后炎症反应的作用,及其保护机制的研究仍然比较缺乏。本实验旨在研究TanⅡA是否对大鼠心肌梗死后的炎症反应有干预作用,并探讨其可能的作用机制。
本实验分为两个部分,第一部分从整体动物水平研究TanⅡA对大鼠心肌梗死后病理变化及炎症反应的作用。方法:实验采用永久性冠状动脉结扎法(LAD)造模,动物分为模型组,药物治疗组和假手术组,造模后1周采集血流动力学数据并取材,进行血清生化指标,病理切片,基因及蛋白水平的研究;结果:TanⅡA(60 mg/kg,灌胃给药)可显著改善梗死后的心脏功能,减少梗死面积及胶原沉积;分子水平的研究表明TanⅡA可以显著减少炎症相关基因MCP-1、TGF-β_1、TNF-α的表达以及其蛋白表达,同时还能够减少核因子NF-κB在细胞核中的表达。结论:TanⅡA对大鼠心肌梗死损伤有很好的保护作用,该作用与其对炎症因子MCP-1、TGF-β_1、TNF-α以及核因子NF-κB的抑制作用相关。
第二部分从细胞水平研究TanⅡA的抗炎作用机制。方法:分别培养SD大鼠乳鼠原代心肌细胞和成纤维细胞,采用TNF-α刺激造模,并在造模24小时后测定细胞上清及细胞中炎症相关蛋白表达。Transwell法检测MCP-1诱导的人单核细胞(THP-1)的趋化实验。结果:TanⅡA可以抑制大鼠心脏成纤维细胞的MCP-1、TGF-β_1的表达,且呈剂量依赖性抑制作用。同时TanⅡA还可以提高心肌细胞表达TGF-β_1,但对心肌细胞表达MCP-1无明显改善作用。TanⅡA对MCP-1诱导的单核细胞趋化性无明显抑制作用。结论:TanⅡA可以减轻由TNF-α引起的炎症因子MCP-1的表达,同时可以通过调节TGF-β_1保护心肌细胞,减轻纤维化。虽然TanⅡA对MCP-1诱导的单核细胞趋化性没有明显抑制作用,但能够降低单核细胞的活性,从而缓解心肌梗死后的炎症损伤。
Ischemic heart disease is a serious illness harmful to human health.Danshen is a commonly used traditional Chinese medicine for the treatment of cardiovascular diseases.Tanshinone IIA(Tan IIA),as a key compound of Danshen,has been proved to protect the cardiovascular diseases.But the report of Tan IIA to treat myocardium infarction is rare.Present study was performed to investigate whether Tan IIA,which has shown cardio protective capacity on myocardial ischemia,has the effects of inhibiting the inflammatory responses following myocardial infarction and its potential mechanisms.
This experiment contains two parts.The first part was to measure the cardio-protect effects of Tan IIA in vivo.Method:Rat myocardial infarction(MI) model was induced by permanent left anterior descending coronary artery(LAD) ligation.After the operation rats were divided into three groups(sham,MI and Tan IIA).One week later,haemodynamics data were determined,and then rats were killed to collect the samples for serum biochemical analysis,pathology analysis,gene and protein analysis.Result:Administration of MI rats with Tan IIA(60 mg/kg/d) attenuated the MI pathological changes and improved the heart function,reduced expression of MCP-1,TGF-β_1 and macrophage infiltration in infracted border zone of myocardium.Furthermore,Tan IIA could also decrease the expression of TNF-αand activation of NF-κB.Conclusion:Tan IIA could markedly reduce myocardial infarction induced myocardium injury.This may be attribute to its inhibiting effects on MCP-1、TGF-β_1、TNF-αand NF-κB.
The second part was to measure the cardio-protect effects of Tan IIA in vitro. Method:Inflammatory model was established by TNF-αstimuli on cardiacmyocyte and cardiac fibroblast.MCP-1 induced monocyte chemotaxis was measured by using a transwell plate.Then,the effect of TanII A on inflammation and chemotaxis were analyzed.Result:Tan IIA could reduce MCP-1 and TGF-bbbbbb_1 secretion of cardiac fibroblasts in a dose dependent manner,and could increase TGF-bbbbbb_1 secretion in cardiacmyocyte.But Tan IIA can't significantly inhibit MCP-1 induced transmigration of THP-1 cells.Conclusion:Tan IIA could reduce TNF-aaaaaaaaaa induced MCP-1 expression, protect cardiacmyocyte and reduce fibrosis.Though Tan IIA can't significantly inhibit MCP-1 induced transmigration of THP-1 cells,it can decrease the activity of THP-1 cell.
本实验分为两个部分,第一部分从整体动物水平研究TanⅡA对大鼠心肌梗死后病理变化及炎症反应的作用。方法:实验采用永久性冠状动脉结扎法(LAD)造模,动物分为模型组,药物治疗组和假手术组,造模后1周采集血流动力学数据并取材,进行血清生化指标,病理切片,基因及蛋白水平的研究;结果:TanⅡA(60 mg/kg,灌胃给药)可显著改善梗死后的心脏功能,减少梗死面积及胶原沉积;分子水平的研究表明TanⅡA可以显著减少炎症相关基因MCP-1、TGF-β_1、TNF-α的表达以及其蛋白表达,同时还能够减少核因子NF-κB在细胞核中的表达。结论:TanⅡA对大鼠心肌梗死损伤有很好的保护作用,该作用与其对炎症因子MCP-1、TGF-β_1、TNF-α以及核因子NF-κB的抑制作用相关。
第二部分从细胞水平研究TanⅡA的抗炎作用机制。方法:分别培养SD大鼠乳鼠原代心肌细胞和成纤维细胞,采用TNF-α刺激造模,并在造模24小时后测定细胞上清及细胞中炎症相关蛋白表达。Transwell法检测MCP-1诱导的人单核细胞(THP-1)的趋化实验。结果:TanⅡA可以抑制大鼠心脏成纤维细胞的MCP-1、TGF-β_1的表达,且呈剂量依赖性抑制作用。同时TanⅡA还可以提高心肌细胞表达TGF-β_1,但对心肌细胞表达MCP-1无明显改善作用。TanⅡA对MCP-1诱导的单核细胞趋化性无明显抑制作用。结论:TanⅡA可以减轻由TNF-α引起的炎症因子MCP-1的表达,同时可以通过调节TGF-β_1保护心肌细胞,减轻纤维化。虽然TanⅡA对MCP-1诱导的单核细胞趋化性没有明显抑制作用,但能够降低单核细胞的活性,从而缓解心肌梗死后的炎症损伤。
Ischemic heart disease is a serious illness harmful to human health.Danshen is a commonly used traditional Chinese medicine for the treatment of cardiovascular diseases.Tanshinone IIA(Tan IIA),as a key compound of Danshen,has been proved to protect the cardiovascular diseases.But the report of Tan IIA to treat myocardium infarction is rare.Present study was performed to investigate whether Tan IIA,which has shown cardio protective capacity on myocardial ischemia,has the effects of inhibiting the inflammatory responses following myocardial infarction and its potential mechanisms.
This experiment contains two parts.The first part was to measure the cardio-protect effects of Tan IIA in vivo.Method:Rat myocardial infarction(MI) model was induced by permanent left anterior descending coronary artery(LAD) ligation.After the operation rats were divided into three groups(sham,MI and Tan IIA).One week later,haemodynamics data were determined,and then rats were killed to collect the samples for serum biochemical analysis,pathology analysis,gene and protein analysis.Result:Administration of MI rats with Tan IIA(60 mg/kg/d) attenuated the MI pathological changes and improved the heart function,reduced expression of MCP-1,TGF-β_1 and macrophage infiltration in infracted border zone of myocardium.Furthermore,Tan IIA could also decrease the expression of TNF-αand activation of NF-κB.Conclusion:Tan IIA could markedly reduce myocardial infarction induced myocardium injury.This may be attribute to its inhibiting effects on MCP-1、TGF-β_1、TNF-αand NF-κB.
The second part was to measure the cardio-protect effects of Tan IIA in vitro. Method:Inflammatory model was established by TNF-αstimuli on cardiacmyocyte and cardiac fibroblast.MCP-1 induced monocyte chemotaxis was measured by using a transwell plate.Then,the effect of TanII A on inflammation and chemotaxis were analyzed.Result:Tan IIA could reduce MCP-1 and TGF-bbbbbb_1 secretion of cardiac fibroblasts in a dose dependent manner,and could increase TGF-bbbbbb_1 secretion in cardiacmyocyte.But Tan IIA can't significantly inhibit MCP-1 induced transmigration of THP-1 cells.Conclusion:Tan IIA could reduce TNF-aaaaaaaaaa induced MCP-1 expression, protect cardiacmyocyte and reduce fibrosis.Though Tan IIA can't significantly inhibit MCP-1 induced transmigration of THP-1 cells,it can decrease the activity of THP-1 cell.
引文
1 Marban E.Cardiac channelopathies.Nature 2002;45;213-8.
2 Alam S E,Nasser S S,Fernainy K E,et al.Cytokine imbalance in acute coronary syndrome.Current Opinion in Pharmacology 2004,4:166-170.
3 Frangogiannis N G,Smith C W,Entman M L.The inflammatory response in myocardial infarction.Cardiovasc Res.2002,53:31-47.
4 Sasayama S,Okada M,Matsumori A.Chemokines and cardiovascular diseases.Cardiovasc Res.2000,45:267-9.
5 Capers Qt,Alexander RW,Lou P,et al.Monocyte chemoattractant protein-1expression in aortic tissues of hypertensive rats.Hypertension.1997,30:1397-402.
6 Shioi T,Matsumori A,Kihara Y,et al.Increased expression of interleukin-1 beta and monocyte chemotactic and activating factor/ monocyte chemoattractant protein-1in the hypertrophied and failing heart with pressure overload.Circ Res.1997,81:664-71.
7 Aukrust P,Ueland T,Muller F,et al.Elevated circulating levels of C-C chemokines in patients with congestive heart failure.Circulation.1998,97:1136-43.
8 Egashira K,Koyanagi M,Kitamoto S,et al.Anti-monocyte chemoattractant protein-1 gene therapy inhibits vascular remodeling in rats:blockade of MCP-1activity after intramuscular transfer of a mutant gene inhibits vascular remodeling induced by chronic blockade of NO synthesis.FASEB J.2000,14:1974-8.
9 Kolattukudy PE,Quasch T,Berges S.Myocarditis induced by targeted expression of the MCP-1 gene in murine cardiac muscle.Am J Pathol 1998,152:101-11.
10 Kakio T,Matsumori A,Ono K,et al.Roles and relationship of macrophages and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in the ischemic and reperfused rat heart.Lab Invest.2000,80:1127-36.
11 Behr TM,Wang X,Aiyar N,et al.Monocyte chemoattractant protein-1 is upregulated in rats with volume:overload congestive heart failure.Circulation.2000,102:1315-22.
12 Rollins BJ,Yoshimura T,Leonard EJ,et al.Cytokine-activated human endothelial cells synthesize and secrete a monocyte chemoattractant,MCP-1/JE.Am J Pathol.1990,136:1229-33.
13 国家药典委员会,中华人民共和国药典2005年版一部,化学工业出版社,2005(1):52
14 Fu J,Huang H,Liu J,Pi R,Chen J,Liu P.Tanshinone IIA protects cardiacmyocytes against oxidative stress-triggered damage and apoptosis.Eur J.Pharmacol.2007,568,213-221.
15 Krzemi(?)ski TF,Nozy(?)ski JK,Grzyb J,Porc M.Wide-spread myocardial remodeling after acute myocardial infarction in rat. Features for heart failure progression. Vascul Pharmacol. 2008, 48(2-3): 100-8.
16 Parikh SV, de Lemos JA. Biomarkers in cardiovascular disease: integrating pathophysiology into clinical practice. Am J Med Sci. 2006, 32(4): 186-97.
17 Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008, 117(2):244-79.
18 Lu L, Chen SS, Zhang JQ, Ramires FJ, Sun Y. Activation of nuclear factor-kappaB and its proinflammatory mediator cascade in the infarcted rat heart. Biochem Biophys Res Commun. 2004, 321(4):879-85.
19 Xia Y, Frangogiannis NG MCP-1/CCL2 as a therapeutic target in myocardial infarction and ischemic cardiomyopathy. Inflamm Allergy Drug Targets. 2007, 6(2):101-7.
20 Kobusiak-Prokopowicz M, Orzeszko J, Mazur G, Mysiak A, Orda A, Poreba R, Mazurek W. Chemokines and left ventricular function in patients with acute myocardial infarction. Eur J Intern Med. 2007, 18(4):288-94.
21 Vogel CF, Nishirnura N, Sciullo E, Wong P, Li W, Matsumura F. Modulation of the chemokines KC and MCP-1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Arch Biochem Biophys. 2007, 461(2):169-75.
22 Gao X, Iwai M, Inaba S, Tomono Y, Kanno H, Mogi M, Horiuchi M. Attenuation of monocyte chemoattractant protein-1 expression via inhibition of nuclear factor-kappaB activity in inflammatory vascular injury. Am J Hypertens. 2007, 20(11):1170-5.
23 Clifton DR, Rydkina E, Huyck H, Pryhuber G, Freeman RS, Silverman DJ, Sahni SK. Expression and secretion of chemotactic cytokines IL-8 and MCP-1 by human endothelial cells after Rickettsia rickettsii infection: regulation by nuclear transcription factor NF-kappaB. Int J Med Microbiol. 2005, 295(4):267-78.
24 Libby P. Inflammation in atherosclerosis. Nature. 2002, 420(6917):868-74.
25 Batista ML Jr, Santos RV, Cunha LM, Mattos K, Oliveira EM, Seelaender MC, Costa Rosa LF. Changes in the pro-inflammatory cytokine production and peritoneal macrophage function in rats with chronic heart failure. Cytokine. 2006, 34(5-6):284-90.
26 Ren G, Dewald O, Frangogiannis NG Inflammatory mechanisms in myocardial infarction. Curr Drug Targets Inflamm Allergy. 2003, 2(3):242-56.
27 Amy Wing Yin Ho, Chun Kwok Wong, Christopher Wai Kei Lam. Tumor necrosis factor-a up-regulates the expression of CCL2 and adhesion molecules of human proximal tubular epithelial cells through MAPK signaling pathways.Immunobiology.2008, 213(7):533-44.
28 Marino M, Scuderi F, Provenzano C, Scheller J, Rose-John S, Bartoccioni E. IL-6 regulates MCP-1, ICAM-1 and IL-6 expression in human myoblasts. J Neuroimmunol. 2008, 196(1-2):41-8.
29 Takahashi M, Suzuki E, Takeda R, Oba S, Nishimatsu H, Kimura K, Nagano T, Nagai R, Hirata Y. Angiotensin II and Tumor Necrosis Factor-{alpha} Synergistically Promote Monocyte Chemoattractant Protein-1 Expression: Roles of NF {kappa} B, p38 and Reactive Oxygen Species. Am J Physiol Heart Circ Physiol. 2008, 294(6):H2879-88.
30 Guo YJ, Li WH, Wu R, Xie Q, Cui LQ. ACE2 overexpression inhibits angiotensin II-induced monocyte chemoattractant protein-1 expression in macrophages. Arch Med Res. 2008, 39(2): 149-54.
31 Zhou L, Azfer A, Niu J, Graham S, Choudhury M, Adamski FM, Younce C, Binkley PF, Kolattukudy PE. Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction. Circ Res. 2006, 98(9): 1177-85.
32 Niu J, Azfer A, Zhelyabovska O, Fatma S, Kolattukudy PE. Monocyte chemotactic protein (MCP)-1 promotes angiogenesis via a novel transcription factor, MCP-1-induced protein (MCPIP). J Biol Chem. 2008, 283(21): 14542-51.
33 Morimoto H, Hirose M, Takahashi M, Kawaguchi M, Ise H, Kolattukudy PE, Yamada M, Ikeda U. MCP-1 induces cardioprotection against ischaemia/reperfusion injury: role of reactive oxygen species. Cardiovasc Res. 2008, 78(3):554-62.
34 Bujak M, Frangogiannis NG The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 2007, 74(2): 184-95.
35 Lutgens E, Gijbels M, Smook M, Heeringa P, Gotwals P, Koteliansky VE, Daemen MJ. Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. Arterioscler Thromb Vasc Biol. 2002, 22(6):975-82.
36 Matsumoto-Ida M, Takimoto Y, Aoyama T, Akao M, Takeda T, Kita T. Activation of TGF-beta1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats. Am J Physiol Heart Circ Physiol. 2006, 290(2):H709-15.
37 Manicone AM, McGuire JK. Matrix metalloproteinases as modulators of inflammation. Semin Cell Dev Biol. 2008,19(1):34-41.
38 Kintscher U, Goetze S, Wakino S, Kim S, Nagpal S, Chandraratna RA, Graf K, Fleck E, Hsueh WA, Law RE. Peroxisome proliferator-activated receptor and retinoid X receptor ligands inhibit monocyte chemotactic protein-1-directed migration of monocytes. Eur J Pharmacol. 2000, 401(3):259-70.
39 Wayman NS, Hattori Y, McDonald MC, Mota-Filipe H, Cuzzocrea S, Pisano B, Chatterjee PK, Thiemermann C. Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J. 2002, 16(9): 1027-40.
40 Gong Z, Huang C, Sheng X, Zhang Y, Li Q, Wang MW, Peng L, Zang YQ. The role of tanshinone IIA in the treatment of obesity through peroxisome proliferator-activated receptor gamma antagonism. Endocrinology. 2009, 150(1):104-13.
41 Ieda M, Tsuchihashi T, Ivey KN, Ross RS, Hong TT, Shaw RM, Srivastava D. Cardiac fibroblasts regulate myocardial proliferation through betal integrin signaling. Dev Cell. 2009, 16(2):233-44.
42 Hohensinner PJ, Kaun C, Rychli K, Ben-Tal Cohen E, Kastl SP, Demyanets S, Pfaffenberger S, Speidl WS, Rega G, Ullrich R, Maurer G, Huber K, Wojta J. Monocyte chemoattractant protein (MCP-1) is expressed in human cardiac cells and is differentially regulated by inflammatory mediators and hypoxia. FEBS Lett. 2006, 580(14):3532-8.
43 Hayashidani S, Tsutsui H, Shiomi T, Ikeuchi M, Matsusaka H, Suematsu N, Wen J, Egashira K, Takeshita A. Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation. 2003, 108(17):2134-40.
44 Ban K, Ikeda U, Takahashi M, Kanbe T, Kasahara T, Shimada K. Expression of intercellular adhesion molecule-1 on rat cardiac myocytes by monocyte chemoattractant protein-1. Cardiovasc Res. 1994, 28(8): 1258-62.
45 Gharaee-Kermani M, Denholm EM, Phan SH. Costimulation of fibroblast collagen and transforming growth factor betal gene expression by monocyte chemoattractant protein-1 via specific receptors. J Biol Chem. 1996, 271(30):17779-84.
46 Kumar A, Kumar A, Paladugu B, Mensing J, Parrillo JE. Transforming growth factor-beta1 blocks in vitro cardiac myocyte depression induced by tumor necrosis factor-alpha, interleukin-1beta, and human septic shock serum. Crit Care Med. 2007 Feb;35(2):358-64.
47 Jang SI, Kim HJ, Kim YJ, Jeong SI, You YO. Tanshinone IIA inhibits LPS-induced NF-kappaB activation in RAW 264.7 cells: possible involvement of the NIK-IKK, ERK1/2, p38 and JNK pathways. Eur J Pharmacol. 2006, 542(1-3):1-7.
48 Tsang CM, Wong CK, Ip WK, Lam CW. Synergistic effect of SCF and TNF-alpha on the up-regulation of cell-surface expression of ICAM-1 on human leukemic mast cell line (HMC)-1 cells. J Leukoc Biol. 2005, 78(1):239-47.
49 Wong CK, Ip WK, Lam CW. Biochemical assessment of intracellular signal transduction pathways in eosinophils: implications for pharmacotherapy. Crit Rev Clin Lab Sci. 2004, 41(1):79-113.
50 Zhang X, Azhar G, Nagano K, Wei JY. Differential vulnerability to oxidative stress in rat cardiac myocytes versus fibroblasts. J Am Coll Cardiol. 2001, 38(7):2055-62.
51 Liu JJ, Zhang Y, Lin DJ, Xiao RZ. Tanshinone IIA inhibits leukemia THP-1 cell growth by induction of apoptosis.Oncol Rep.2009,21(4):1075-81.
1 Krzeminski TF,Nozynski JK,Grzyb J,Porc M.Wide-spread myocardial remodeling after acute myocardial infarction in rat.Features for heart failure progression.Vascul Pharmacol,2008,48(2-3):100-108.
2 Batista ML Jr,Santos RV,Cunha LM,Mattos K,Oliveira EM,Seelaender MC,et al.Changes in the pro-inflammatory cytokine production and peritoneal macrophage function in rats with chronic heart failure.Cytokine,2006,34(5-6):284-290.
3 Ren G,Dewald O,Frangogiannis NG Inflammatory mechanisms in myocardial infarction.Curr Drug Targets Inflamm Allergy,2003,2(3):242-256.
4 Lu L,Zhang JQ,Ramires FJ,Sun Y.Molecular and cellular events at the site of myocardial infarction:from the perspective of rebuilding myocardial tissue.Biochem Biophys Res Commun,2004,320(3):907-913.
5 Li Z,Ma JY,Kerr I,Chakravarty S,Dugar S,Schreiner G,et al.Selective inhibition of p38alpha MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury.Am J Physiol Heart Circ Physiol,2006,291(4):H1972-1977.
6 Lu L, Chen SS, Zhang JQ, Ramires FJ, Sun Y. Activation of nuclear factor-kappaB and its proinflammatory mediator cascade in the infarcted rat heart. Biochem Biophys Res Commun, 2004, 321(4):879-885.
7 Vogel CF, Nishimura N, Sciullo E, Wong P, Li W, Matsumura F.Modulation of the chemokines KC and MCP-1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Arch Biochem Biophys, 2007,461(2):169-175.
8 Kobusiak-Prokopowicz M, Orzeszko J, Mazur G, Mysiak A, Orda A, Poreba R, et al. Chemokines and left ventricular function in patients with acute myocardial infarction. Eur J Intern Med, 2007, 18(4):288-294.
9 Niu J, Azfer A, Deucher MF, Goldschmidt-Clermont PJ, Kolattukudy PE. Targeted cardiac expression of soluble Fas prevents the development of heart failure in mice with cardiac-specific expression of MCP-1. J Mol Cell Cardiol, 2006,40(6):810-820.
10 Guo YJ, Li WH, Wu R, Xie Q, Cui LQ.ACE2 overexpression inhibits angiotensin Il-induced monocyte chemoattractant protein-1 expression in macrophages. Arch Med Res, 2008, 39(2):149-154.
11 Hayashidani S, Tsutsui H, Shiomi T, Ikeuchi M, Matsusaka H, Suematsu N, et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation, 2003, 108(17):2134-2140.
12 Ban K, Ikeda U, Takahashi M, Kanbe T, Kasahara T, Shimada K. Expression of intercellular adhesion molecule-1 on rat cardiac myocytes by monocyte chemoattractant protein-1. Cardiovasc Res, 1994, 28(8):1258-1262.
13 Amy Wing Yin Ho, Chun Kwok Wong, Christopher Wai Kei Lam. Tumor necrosis factor-a up-regulates the expression of CCL2 and adhesion molecules of human proximal tubular epithelial cells through MAPK signaling pathways.Immunobiology,2008,213(7):533-44.
14 Takahashi M, Suzuki E, Takeda R, Oba S, Nishimatsu H, Kimura K, et al. Angiotensin II and Tumor Necrosis Factor-{alpha} Synergistically Promote Monocyte Chemoattractant Protein-1 Expression: Roles of NF {kappa} B, p38 and Reactive Oxygen Species. Am J Physiol Heart Circ PhysiolL, 2008, 294(6):H2879-2888.
15 Arefieva TI, Kukhtina NB, Antonova OA, Krasnikova TL. MCP-1-stimulated chemotaxis of monocytic and endothelial cells is dependent on activation of different signaling cascades. Cytokine, 2005, 31(6):439-446.
16 Dewald O, Zymek P, Winkelmann K, Koerting A, Ren G, Abou-Khamis T,et al. CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res, 2005, 96(8):881 -889.
17 Gavrilin MA, Deucher MF, Boeckman F, Kolattukudy PE. Monocyte chemotactic protein 1 upregulates IL-1beta expression in human monocytes. Biochem Biophys Res Commun, 2000, 277(1):37-42.
18 Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res, 2002, 90(3):251-262.
19 Bujak M, Frangogiannis NG The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res, 2007,74(2):184-195.
20 McQuibban GA, Gong JH, Wong JP, Wallace JL, Clark-Lewis I, Overall CM. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood, 2002, 100(4): 1160-1167.
21 Kaikita K, Hayasaki T, Okuma T, Kuziel WA, Ogawa H, Takeya M. Targeted deletion of CC chemokine receptor 2 attenuates left ventricular remodeling after experimental myocardial infarction. Am J Pathol, 2004, 165(2):439-447.
22 Schwarz ER, Meven DA, Sulemanjee NZ, Kersting PH, Tussing T, Skobel EC, et al. Monocyte chemoattractant protein 1-induced monocyte infiltration produces angiogenesis but not arteriogenesis in chronically infarcted myocardium. J Cardiovasc Pharmacol Ther,2004,9(4):279-289.
23 Morimoto H,Hirose M,Takahashi M,Kawaguchi M,Ise H,Kolattukudy PE,et al.MCP-1 induces cardioprotection against ischaemia/reperfusion injury:role of reactive oxygen species.Cardiovasc Res,2008,78(3):554-562.
24 Gao X,Iwai M,Inaba S,Tomono Y,Kanno H,Mogi M,et al.Attenuation of monocyte chemoattractant protein-1 expression via inhibition of nuclear factor-kappaB activity in inflammatory vascular injury.Am J Hypertens.2007,20(11):1170-1175.
25 Zineh I,Luo X,Welder GJ,Debella AE,Wessel TR,Arant CB,et al.Modulatory effects of atorvastatin on endothelial cell-derived chemokines,cytokines,and angiogenic factors.Pharmacotherapy,2006,26(3):333-340.
26 Zelvyte I,Dominaitiene R,Crisby M,Janciauskiene S.Modulation of inflammatory mediators and PPARgamma and NFkappaB expression by pravastatin in response to lipoproteins in human monocytes in vitro.Pharmacol Res,2002,45(2):147-154.
27 张学凯,赵宗江,崔秀明,张新雪,杨美娟.Rg1、Rb1对糖尿病肾病大鼠肾脏保护作用及其对肾组织MCP-1 mRNA与蛋白表达的影响.中国中西医结合肾病杂志,2008,9(7):578-581.
28 李浩,刘开祥,俸军林.丹参酮IIA对鼠脑缺血再灌注损伤MCP-1和IL-1β含量的影响.中国中医急症,2008,17(7):957-958.
29 Zhu J,Yong W,Wu X,Yu Y,Lv J,Liu C,et al.Anti-inflammatory effect of resveratrol on TNF-alpha-induced MCP-1 expression in adipocytes.Biochem Biophys Res Commun,2008,369(2):471-477.
2 Alam S E,Nasser S S,Fernainy K E,et al.Cytokine imbalance in acute coronary syndrome.Current Opinion in Pharmacology 2004,4:166-170.
3 Frangogiannis N G,Smith C W,Entman M L.The inflammatory response in myocardial infarction.Cardiovasc Res.2002,53:31-47.
4 Sasayama S,Okada M,Matsumori A.Chemokines and cardiovascular diseases.Cardiovasc Res.2000,45:267-9.
5 Capers Qt,Alexander RW,Lou P,et al.Monocyte chemoattractant protein-1expression in aortic tissues of hypertensive rats.Hypertension.1997,30:1397-402.
6 Shioi T,Matsumori A,Kihara Y,et al.Increased expression of interleukin-1 beta and monocyte chemotactic and activating factor/ monocyte chemoattractant protein-1in the hypertrophied and failing heart with pressure overload.Circ Res.1997,81:664-71.
7 Aukrust P,Ueland T,Muller F,et al.Elevated circulating levels of C-C chemokines in patients with congestive heart failure.Circulation.1998,97:1136-43.
8 Egashira K,Koyanagi M,Kitamoto S,et al.Anti-monocyte chemoattractant protein-1 gene therapy inhibits vascular remodeling in rats:blockade of MCP-1activity after intramuscular transfer of a mutant gene inhibits vascular remodeling induced by chronic blockade of NO synthesis.FASEB J.2000,14:1974-8.
9 Kolattukudy PE,Quasch T,Berges S.Myocarditis induced by targeted expression of the MCP-1 gene in murine cardiac muscle.Am J Pathol 1998,152:101-11.
10 Kakio T,Matsumori A,Ono K,et al.Roles and relationship of macrophages and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in the ischemic and reperfused rat heart.Lab Invest.2000,80:1127-36.
11 Behr TM,Wang X,Aiyar N,et al.Monocyte chemoattractant protein-1 is upregulated in rats with volume:overload congestive heart failure.Circulation.2000,102:1315-22.
12 Rollins BJ,Yoshimura T,Leonard EJ,et al.Cytokine-activated human endothelial cells synthesize and secrete a monocyte chemoattractant,MCP-1/JE.Am J Pathol.1990,136:1229-33.
13 国家药典委员会,中华人民共和国药典2005年版一部,化学工业出版社,2005(1):52
14 Fu J,Huang H,Liu J,Pi R,Chen J,Liu P.Tanshinone IIA protects cardiacmyocytes against oxidative stress-triggered damage and apoptosis.Eur J.Pharmacol.2007,568,213-221.
15 Krzemi(?)ski TF,Nozy(?)ski JK,Grzyb J,Porc M.Wide-spread myocardial remodeling after acute myocardial infarction in rat. Features for heart failure progression. Vascul Pharmacol. 2008, 48(2-3): 100-8.
16 Parikh SV, de Lemos JA. Biomarkers in cardiovascular disease: integrating pathophysiology into clinical practice. Am J Med Sci. 2006, 32(4): 186-97.
17 Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008, 117(2):244-79.
18 Lu L, Chen SS, Zhang JQ, Ramires FJ, Sun Y. Activation of nuclear factor-kappaB and its proinflammatory mediator cascade in the infarcted rat heart. Biochem Biophys Res Commun. 2004, 321(4):879-85.
19 Xia Y, Frangogiannis NG MCP-1/CCL2 as a therapeutic target in myocardial infarction and ischemic cardiomyopathy. Inflamm Allergy Drug Targets. 2007, 6(2):101-7.
20 Kobusiak-Prokopowicz M, Orzeszko J, Mazur G, Mysiak A, Orda A, Poreba R, Mazurek W. Chemokines and left ventricular function in patients with acute myocardial infarction. Eur J Intern Med. 2007, 18(4):288-94.
21 Vogel CF, Nishirnura N, Sciullo E, Wong P, Li W, Matsumura F. Modulation of the chemokines KC and MCP-1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Arch Biochem Biophys. 2007, 461(2):169-75.
22 Gao X, Iwai M, Inaba S, Tomono Y, Kanno H, Mogi M, Horiuchi M. Attenuation of monocyte chemoattractant protein-1 expression via inhibition of nuclear factor-kappaB activity in inflammatory vascular injury. Am J Hypertens. 2007, 20(11):1170-5.
23 Clifton DR, Rydkina E, Huyck H, Pryhuber G, Freeman RS, Silverman DJ, Sahni SK. Expression and secretion of chemotactic cytokines IL-8 and MCP-1 by human endothelial cells after Rickettsia rickettsii infection: regulation by nuclear transcription factor NF-kappaB. Int J Med Microbiol. 2005, 295(4):267-78.
24 Libby P. Inflammation in atherosclerosis. Nature. 2002, 420(6917):868-74.
25 Batista ML Jr, Santos RV, Cunha LM, Mattos K, Oliveira EM, Seelaender MC, Costa Rosa LF. Changes in the pro-inflammatory cytokine production and peritoneal macrophage function in rats with chronic heart failure. Cytokine. 2006, 34(5-6):284-90.
26 Ren G, Dewald O, Frangogiannis NG Inflammatory mechanisms in myocardial infarction. Curr Drug Targets Inflamm Allergy. 2003, 2(3):242-56.
27 Amy Wing Yin Ho, Chun Kwok Wong, Christopher Wai Kei Lam. Tumor necrosis factor-a up-regulates the expression of CCL2 and adhesion molecules of human proximal tubular epithelial cells through MAPK signaling pathways.Immunobiology.2008, 213(7):533-44.
28 Marino M, Scuderi F, Provenzano C, Scheller J, Rose-John S, Bartoccioni E. IL-6 regulates MCP-1, ICAM-1 and IL-6 expression in human myoblasts. J Neuroimmunol. 2008, 196(1-2):41-8.
29 Takahashi M, Suzuki E, Takeda R, Oba S, Nishimatsu H, Kimura K, Nagano T, Nagai R, Hirata Y. Angiotensin II and Tumor Necrosis Factor-{alpha} Synergistically Promote Monocyte Chemoattractant Protein-1 Expression: Roles of NF {kappa} B, p38 and Reactive Oxygen Species. Am J Physiol Heart Circ Physiol. 2008, 294(6):H2879-88.
30 Guo YJ, Li WH, Wu R, Xie Q, Cui LQ. ACE2 overexpression inhibits angiotensin II-induced monocyte chemoattractant protein-1 expression in macrophages. Arch Med Res. 2008, 39(2): 149-54.
31 Zhou L, Azfer A, Niu J, Graham S, Choudhury M, Adamski FM, Younce C, Binkley PF, Kolattukudy PE. Monocyte chemoattractant protein-1 induces a novel transcription factor that causes cardiac myocyte apoptosis and ventricular dysfunction. Circ Res. 2006, 98(9): 1177-85.
32 Niu J, Azfer A, Zhelyabovska O, Fatma S, Kolattukudy PE. Monocyte chemotactic protein (MCP)-1 promotes angiogenesis via a novel transcription factor, MCP-1-induced protein (MCPIP). J Biol Chem. 2008, 283(21): 14542-51.
33 Morimoto H, Hirose M, Takahashi M, Kawaguchi M, Ise H, Kolattukudy PE, Yamada M, Ikeda U. MCP-1 induces cardioprotection against ischaemia/reperfusion injury: role of reactive oxygen species. Cardiovasc Res. 2008, 78(3):554-62.
34 Bujak M, Frangogiannis NG The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 2007, 74(2): 184-95.
35 Lutgens E, Gijbels M, Smook M, Heeringa P, Gotwals P, Koteliansky VE, Daemen MJ. Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. Arterioscler Thromb Vasc Biol. 2002, 22(6):975-82.
36 Matsumoto-Ida M, Takimoto Y, Aoyama T, Akao M, Takeda T, Kita T. Activation of TGF-beta1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats. Am J Physiol Heart Circ Physiol. 2006, 290(2):H709-15.
37 Manicone AM, McGuire JK. Matrix metalloproteinases as modulators of inflammation. Semin Cell Dev Biol. 2008,19(1):34-41.
38 Kintscher U, Goetze S, Wakino S, Kim S, Nagpal S, Chandraratna RA, Graf K, Fleck E, Hsueh WA, Law RE. Peroxisome proliferator-activated receptor and retinoid X receptor ligands inhibit monocyte chemotactic protein-1-directed migration of monocytes. Eur J Pharmacol. 2000, 401(3):259-70.
39 Wayman NS, Hattori Y, McDonald MC, Mota-Filipe H, Cuzzocrea S, Pisano B, Chatterjee PK, Thiemermann C. Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J. 2002, 16(9): 1027-40.
40 Gong Z, Huang C, Sheng X, Zhang Y, Li Q, Wang MW, Peng L, Zang YQ. The role of tanshinone IIA in the treatment of obesity through peroxisome proliferator-activated receptor gamma antagonism. Endocrinology. 2009, 150(1):104-13.
41 Ieda M, Tsuchihashi T, Ivey KN, Ross RS, Hong TT, Shaw RM, Srivastava D. Cardiac fibroblasts regulate myocardial proliferation through betal integrin signaling. Dev Cell. 2009, 16(2):233-44.
42 Hohensinner PJ, Kaun C, Rychli K, Ben-Tal Cohen E, Kastl SP, Demyanets S, Pfaffenberger S, Speidl WS, Rega G, Ullrich R, Maurer G, Huber K, Wojta J. Monocyte chemoattractant protein (MCP-1) is expressed in human cardiac cells and is differentially regulated by inflammatory mediators and hypoxia. FEBS Lett. 2006, 580(14):3532-8.
43 Hayashidani S, Tsutsui H, Shiomi T, Ikeuchi M, Matsusaka H, Suematsu N, Wen J, Egashira K, Takeshita A. Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation. 2003, 108(17):2134-40.
44 Ban K, Ikeda U, Takahashi M, Kanbe T, Kasahara T, Shimada K. Expression of intercellular adhesion molecule-1 on rat cardiac myocytes by monocyte chemoattractant protein-1. Cardiovasc Res. 1994, 28(8): 1258-62.
45 Gharaee-Kermani M, Denholm EM, Phan SH. Costimulation of fibroblast collagen and transforming growth factor betal gene expression by monocyte chemoattractant protein-1 via specific receptors. J Biol Chem. 1996, 271(30):17779-84.
46 Kumar A, Kumar A, Paladugu B, Mensing J, Parrillo JE. Transforming growth factor-beta1 blocks in vitro cardiac myocyte depression induced by tumor necrosis factor-alpha, interleukin-1beta, and human septic shock serum. Crit Care Med. 2007 Feb;35(2):358-64.
47 Jang SI, Kim HJ, Kim YJ, Jeong SI, You YO. Tanshinone IIA inhibits LPS-induced NF-kappaB activation in RAW 264.7 cells: possible involvement of the NIK-IKK, ERK1/2, p38 and JNK pathways. Eur J Pharmacol. 2006, 542(1-3):1-7.
48 Tsang CM, Wong CK, Ip WK, Lam CW. Synergistic effect of SCF and TNF-alpha on the up-regulation of cell-surface expression of ICAM-1 on human leukemic mast cell line (HMC)-1 cells. J Leukoc Biol. 2005, 78(1):239-47.
49 Wong CK, Ip WK, Lam CW. Biochemical assessment of intracellular signal transduction pathways in eosinophils: implications for pharmacotherapy. Crit Rev Clin Lab Sci. 2004, 41(1):79-113.
50 Zhang X, Azhar G, Nagano K, Wei JY. Differential vulnerability to oxidative stress in rat cardiac myocytes versus fibroblasts. J Am Coll Cardiol. 2001, 38(7):2055-62.
51 Liu JJ, Zhang Y, Lin DJ, Xiao RZ. Tanshinone IIA inhibits leukemia THP-1 cell growth by induction of apoptosis.Oncol Rep.2009,21(4):1075-81.
1 Krzeminski TF,Nozynski JK,Grzyb J,Porc M.Wide-spread myocardial remodeling after acute myocardial infarction in rat.Features for heart failure progression.Vascul Pharmacol,2008,48(2-3):100-108.
2 Batista ML Jr,Santos RV,Cunha LM,Mattos K,Oliveira EM,Seelaender MC,et al.Changes in the pro-inflammatory cytokine production and peritoneal macrophage function in rats with chronic heart failure.Cytokine,2006,34(5-6):284-290.
3 Ren G,Dewald O,Frangogiannis NG Inflammatory mechanisms in myocardial infarction.Curr Drug Targets Inflamm Allergy,2003,2(3):242-256.
4 Lu L,Zhang JQ,Ramires FJ,Sun Y.Molecular and cellular events at the site of myocardial infarction:from the perspective of rebuilding myocardial tissue.Biochem Biophys Res Commun,2004,320(3):907-913.
5 Li Z,Ma JY,Kerr I,Chakravarty S,Dugar S,Schreiner G,et al.Selective inhibition of p38alpha MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury.Am J Physiol Heart Circ Physiol,2006,291(4):H1972-1977.
6 Lu L, Chen SS, Zhang JQ, Ramires FJ, Sun Y. Activation of nuclear factor-kappaB and its proinflammatory mediator cascade in the infarcted rat heart. Biochem Biophys Res Commun, 2004, 321(4):879-885.
7 Vogel CF, Nishimura N, Sciullo E, Wong P, Li W, Matsumura F.Modulation of the chemokines KC and MCP-1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Arch Biochem Biophys, 2007,461(2):169-175.
8 Kobusiak-Prokopowicz M, Orzeszko J, Mazur G, Mysiak A, Orda A, Poreba R, et al. Chemokines and left ventricular function in patients with acute myocardial infarction. Eur J Intern Med, 2007, 18(4):288-294.
9 Niu J, Azfer A, Deucher MF, Goldschmidt-Clermont PJ, Kolattukudy PE. Targeted cardiac expression of soluble Fas prevents the development of heart failure in mice with cardiac-specific expression of MCP-1. J Mol Cell Cardiol, 2006,40(6):810-820.
10 Guo YJ, Li WH, Wu R, Xie Q, Cui LQ.ACE2 overexpression inhibits angiotensin Il-induced monocyte chemoattractant protein-1 expression in macrophages. Arch Med Res, 2008, 39(2):149-154.
11 Hayashidani S, Tsutsui H, Shiomi T, Ikeuchi M, Matsusaka H, Suematsu N, et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation, 2003, 108(17):2134-2140.
12 Ban K, Ikeda U, Takahashi M, Kanbe T, Kasahara T, Shimada K. Expression of intercellular adhesion molecule-1 on rat cardiac myocytes by monocyte chemoattractant protein-1. Cardiovasc Res, 1994, 28(8):1258-1262.
13 Amy Wing Yin Ho, Chun Kwok Wong, Christopher Wai Kei Lam. Tumor necrosis factor-a up-regulates the expression of CCL2 and adhesion molecules of human proximal tubular epithelial cells through MAPK signaling pathways.Immunobiology,2008,213(7):533-44.
14 Takahashi M, Suzuki E, Takeda R, Oba S, Nishimatsu H, Kimura K, et al. Angiotensin II and Tumor Necrosis Factor-{alpha} Synergistically Promote Monocyte Chemoattractant Protein-1 Expression: Roles of NF {kappa} B, p38 and Reactive Oxygen Species. Am J Physiol Heart Circ PhysiolL, 2008, 294(6):H2879-2888.
15 Arefieva TI, Kukhtina NB, Antonova OA, Krasnikova TL. MCP-1-stimulated chemotaxis of monocytic and endothelial cells is dependent on activation of different signaling cascades. Cytokine, 2005, 31(6):439-446.
16 Dewald O, Zymek P, Winkelmann K, Koerting A, Ren G, Abou-Khamis T,et al. CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res, 2005, 96(8):881 -889.
17 Gavrilin MA, Deucher MF, Boeckman F, Kolattukudy PE. Monocyte chemotactic protein 1 upregulates IL-1beta expression in human monocytes. Biochem Biophys Res Commun, 2000, 277(1):37-42.
18 Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res, 2002, 90(3):251-262.
19 Bujak M, Frangogiannis NG The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res, 2007,74(2):184-195.
20 McQuibban GA, Gong JH, Wong JP, Wallace JL, Clark-Lewis I, Overall CM. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood, 2002, 100(4): 1160-1167.
21 Kaikita K, Hayasaki T, Okuma T, Kuziel WA, Ogawa H, Takeya M. Targeted deletion of CC chemokine receptor 2 attenuates left ventricular remodeling after experimental myocardial infarction. Am J Pathol, 2004, 165(2):439-447.
22 Schwarz ER, Meven DA, Sulemanjee NZ, Kersting PH, Tussing T, Skobel EC, et al. Monocyte chemoattractant protein 1-induced monocyte infiltration produces angiogenesis but not arteriogenesis in chronically infarcted myocardium. J Cardiovasc Pharmacol Ther,2004,9(4):279-289.
23 Morimoto H,Hirose M,Takahashi M,Kawaguchi M,Ise H,Kolattukudy PE,et al.MCP-1 induces cardioprotection against ischaemia/reperfusion injury:role of reactive oxygen species.Cardiovasc Res,2008,78(3):554-562.
24 Gao X,Iwai M,Inaba S,Tomono Y,Kanno H,Mogi M,et al.Attenuation of monocyte chemoattractant protein-1 expression via inhibition of nuclear factor-kappaB activity in inflammatory vascular injury.Am J Hypertens.2007,20(11):1170-1175.
25 Zineh I,Luo X,Welder GJ,Debella AE,Wessel TR,Arant CB,et al.Modulatory effects of atorvastatin on endothelial cell-derived chemokines,cytokines,and angiogenic factors.Pharmacotherapy,2006,26(3):333-340.
26 Zelvyte I,Dominaitiene R,Crisby M,Janciauskiene S.Modulation of inflammatory mediators and PPARgamma and NFkappaB expression by pravastatin in response to lipoproteins in human monocytes in vitro.Pharmacol Res,2002,45(2):147-154.
27 张学凯,赵宗江,崔秀明,张新雪,杨美娟.Rg1、Rb1对糖尿病肾病大鼠肾脏保护作用及其对肾组织MCP-1 mRNA与蛋白表达的影响.中国中西医结合肾病杂志,2008,9(7):578-581.
28 李浩,刘开祥,俸军林.丹参酮IIA对鼠脑缺血再灌注损伤MCP-1和IL-1β含量的影响.中国中医急症,2008,17(7):957-958.
29 Zhu J,Yong W,Wu X,Yu Y,Lv J,Liu C,et al.Anti-inflammatory effect of resveratrol on TNF-alpha-induced MCP-1 expression in adipocytes.Biochem Biophys Res Commun,2008,369(2):471-477.