辛伐他汀调节p38和CARP与改善大鼠心肌梗死后心肌重塑
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摘要
目的:1.探讨p38丝裂原激活的蛋白激酶(p38MAPK,p38)和心锚重复蛋白(cardiac ankyrin repeat protein,CARP)在大鼠心肌梗死(MI)后的表达变化,及其与MI后心肌重塑的关系;2.探讨辛伐他汀改善心肌重塑的作用是否与p38和CARP有关。
方法:结扎大鼠冠脉前降支致MI,术后24h存活大鼠随机分为MI组(n=25)、p38抑制剂SB203580组(SB组,10μmol/L.kg -1.d -1,n=25)、辛伐他汀组(Sim组,40 mg.kg -1.d -1,n=25)和假手术组(Sham组,n=15)。再将上述各组分为7d和28d二个亚组。各组均测定左心室重量指数(LVWI)、心肌细胞横切面面积(CSA),RT-PCR和免疫组化法测定p38和CARP在心脏的表达。
结果:1. MI组大鼠梗死区心肌细胞严重变性坏死,炎性细胞浸润,大量胶原纤维增生,非梗死区心肌细胞出现代偿性增生肥大;电镜显示,梗死交界区细胞溶解,线粒体明显增多,肌节中断,有明显收缩带肌丝溶解。SB组大鼠病变较轻,Sim组大鼠病变最轻。2. MI组与Sham组相比,前者LVWI和CSA明显增高(P<0.05),p38 mRNA表达无明显改变(P>0.05),但磷酸化p38(p-p38)表达明显升高(P<0.05),CARP mRNA和蛋白在7d时表达升高(P<0.05)。Sim组与MI组相比,前者LVWI和CSA明显降低(P<0.05),p38 mRNA、CARP mRNA、p-p38和CARP蛋白在7d时表达明显降低(P<0.01)。SB组与MI组相比,前者LVWI在7d时明显降低(P<0.01),CSA在7d和28d时均明显减小(P<0.01),p38 mRNA在28d时表达升高,CARP mRNA在7d时表达降低(P<0.01)。SB组与Sim组相比,前者p38 mRNA表达增高(P<0.01),p-p38表达在7d时高于Sim组(P<0.01),CARP表达两组间比较无明显差异(P>0.05)。
结论:
1.大鼠心肌梗死后p38和CARP表达增加;
2.抑制p38可抑制CARP的表达,CARP可能部分受p38信号通路调节;
3.辛伐他汀改善MI后心肌重塑的作用可能与抑制p38和CARP有关。
Objective 1. To investigate the expression mode of p38 mitogen- activated protein kinase (p38MAPK, p38) and Cardiac ankyrin repeat protein (CARP) in rats with myocardial infarction(MI), and its relationship with myocardial remodeling; 2. To investigate the relationship of Simvastatin regulating p38 and CARP with its effect of reversing myocardial remodeling.
Methods Twenty-four hours after the induction of MI, the survival rats were randomly assigned to the following groups: MI group(n=25), p38 inhibiter SB203580 group (10μmol/L.kg-1.d-1,n=25, SB group), Sim group (40 mg.kg-1.d -1,n=25) and Sham group (n=15). Each group was further divided into two subgroups of 7, and 28 days. Left ventricular weight index (LVWI), cardiomyocyte cross-sectional area (CSA) and the expression of p38 and CARP in noninfarcted region of hearts were measured by RT-PCR and immunohistochemistry in each group after the hearts being harvested .
Results 1. In MI group, serious degeneration and necrosis of cardiomyocytes, inflammatory cells infiltration, great acceleration of collagen were observed in infarcted area, and compensatory hypertrophy of cardiomyocytes were observed in noninfarcted area; cytolysis, augmentation of chondrosome in cardiomyocytes and obvious myofilamentlysis at contraction bands were found in electron microscope. In SB group pathological changes was lighter, and the lightest in Sim group compared with MI group. 2. Compared with Sham group, LVWI and CSA significantly increased in MI group (P<0.05); there were no statistical difference of the expression of p38 mRNA in MI group (P>0.05), but the expression of p-p38 significantly elevated (P<0.05); CARP mRNA and protein increased in 7d MI subgroups (P<0.05). Compared with MI group, LVWI and CSA significantly decreased in Sim group (P <0.05); the expression of p38 mRNA, CARP mRNA, p-p38 and CARP protein abated in 7d Sim subgroups (P<0.01). Compared with MI group, LVWI of SB group decreased in 7d subgroup (P<0.01), and CSA decreased in both 7d and 28d SB subgroups (P<0.01); the expression of p38 mRNA increased in 28d SB subgroup, and CARP mRNA decreased in 7d SB subgroup (P<0.01). Compared with Sim group, the expression of p38 mRNA was higher in SB group, and p-p38 higher in 7d SB subgroup (P<0.01).
Conclusion
1. p38 and CARP are upregulated in rats with MI;
2. The inhibition of p38 can downregulate CARP, and CARP is probably regulated partly by p38 signaling pathway;
3. The effect of simvastatin reversing myocardial remodeling is fulfilled, at least partly, through downregulating p38 and CARP.
方法:结扎大鼠冠脉前降支致MI,术后24h存活大鼠随机分为MI组(n=25)、p38抑制剂SB203580组(SB组,10μmol/L.kg -1.d -1,n=25)、辛伐他汀组(Sim组,40 mg.kg -1.d -1,n=25)和假手术组(Sham组,n=15)。再将上述各组分为7d和28d二个亚组。各组均测定左心室重量指数(LVWI)、心肌细胞横切面面积(CSA),RT-PCR和免疫组化法测定p38和CARP在心脏的表达。
结果:1. MI组大鼠梗死区心肌细胞严重变性坏死,炎性细胞浸润,大量胶原纤维增生,非梗死区心肌细胞出现代偿性增生肥大;电镜显示,梗死交界区细胞溶解,线粒体明显增多,肌节中断,有明显收缩带肌丝溶解。SB组大鼠病变较轻,Sim组大鼠病变最轻。2. MI组与Sham组相比,前者LVWI和CSA明显增高(P<0.05),p38 mRNA表达无明显改变(P>0.05),但磷酸化p38(p-p38)表达明显升高(P<0.05),CARP mRNA和蛋白在7d时表达升高(P<0.05)。Sim组与MI组相比,前者LVWI和CSA明显降低(P<0.05),p38 mRNA、CARP mRNA、p-p38和CARP蛋白在7d时表达明显降低(P<0.01)。SB组与MI组相比,前者LVWI在7d时明显降低(P<0.01),CSA在7d和28d时均明显减小(P<0.01),p38 mRNA在28d时表达升高,CARP mRNA在7d时表达降低(P<0.01)。SB组与Sim组相比,前者p38 mRNA表达增高(P<0.01),p-p38表达在7d时高于Sim组(P<0.01),CARP表达两组间比较无明显差异(P>0.05)。
结论:
1.大鼠心肌梗死后p38和CARP表达增加;
2.抑制p38可抑制CARP的表达,CARP可能部分受p38信号通路调节;
3.辛伐他汀改善MI后心肌重塑的作用可能与抑制p38和CARP有关。
Objective 1. To investigate the expression mode of p38 mitogen- activated protein kinase (p38MAPK, p38) and Cardiac ankyrin repeat protein (CARP) in rats with myocardial infarction(MI), and its relationship with myocardial remodeling; 2. To investigate the relationship of Simvastatin regulating p38 and CARP with its effect of reversing myocardial remodeling.
Methods Twenty-four hours after the induction of MI, the survival rats were randomly assigned to the following groups: MI group(n=25), p38 inhibiter SB203580 group (10μmol/L.kg-1.d-1,n=25, SB group), Sim group (40 mg.kg-1.d -1,n=25) and Sham group (n=15). Each group was further divided into two subgroups of 7, and 28 days. Left ventricular weight index (LVWI), cardiomyocyte cross-sectional area (CSA) and the expression of p38 and CARP in noninfarcted region of hearts were measured by RT-PCR and immunohistochemistry in each group after the hearts being harvested .
Results 1. In MI group, serious degeneration and necrosis of cardiomyocytes, inflammatory cells infiltration, great acceleration of collagen were observed in infarcted area, and compensatory hypertrophy of cardiomyocytes were observed in noninfarcted area; cytolysis, augmentation of chondrosome in cardiomyocytes and obvious myofilamentlysis at contraction bands were found in electron microscope. In SB group pathological changes was lighter, and the lightest in Sim group compared with MI group. 2. Compared with Sham group, LVWI and CSA significantly increased in MI group (P<0.05); there were no statistical difference of the expression of p38 mRNA in MI group (P>0.05), but the expression of p-p38 significantly elevated (P<0.05); CARP mRNA and protein increased in 7d MI subgroups (P<0.05). Compared with MI group, LVWI and CSA significantly decreased in Sim group (P <0.05); the expression of p38 mRNA, CARP mRNA, p-p38 and CARP protein abated in 7d Sim subgroups (P<0.01). Compared with MI group, LVWI of SB group decreased in 7d subgroup (P<0.01), and CSA decreased in both 7d and 28d SB subgroups (P<0.01); the expression of p38 mRNA increased in 28d SB subgroup, and CARP mRNA decreased in 7d SB subgroup (P<0.01). Compared with Sim group, the expression of p38 mRNA was higher in SB group, and p-p38 higher in 7d SB subgroup (P<0.01).
Conclusion
1. p38 and CARP are upregulated in rats with MI;
2. The inhibition of p38 can downregulate CARP, and CARP is probably regulated partly by p38 signaling pathway;
3. The effect of simvastatin reversing myocardial remodeling is fulfilled, at least partly, through downregulating p38 and CARP.
引文
[1] Tenhunen O,Rys? J,Ilves M, et a1. Identification of cell cycle regulatory and inflammatory genes as predominant targets of p38 mitogen-activated protein kinase in the heart[J]. Circulation Research, 2006, 99(5):485-493.
[2] becca HR, Lea MD. Cardiac hypertrophy, substrate utilization and metabolic remodeling: cause or effect [J]? Clinical and Experimental Pharmacology and Physiology, 2006, 33(1-2):159–166.
[3] Cheng TH, Shih NL, Chen CH, et a1. Role of mitogen-activated protein kinase pathway in reactive oxygen species-mediated endothelin-1-induced β-myosin heavy chain gene expression and cardiomyocyte hypertrophy [J]. J Biomed Sci, 2005, 12(1): 123-133.
[4] Tsujimoto I, Hikoso S, Yamaguchi O, et a1. The antioxidant edaravone attenuates pressure overload-induced left ventricular hypertrophy [J]. Hypertension,2005,45(5): 921-926.
[5] Zhang D, Gaussin V, Taffet GE, et a1. TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice [J]. Nat Med,2000,6(5):556-563.
[6] Yoko IT, Takashi M, Yoshitoshi K,et a1. Activation of peroxisome proliferator- activated receptor-α? decreases endothelin-1-induced p38 mitogen-activated protein kinase activation in cardiomyocytes [J]. J Cardiovasc Pharmacol, 2004, 44(suppl 1) : S358–S361.
[7] Prakash P, Watanabe K, Hirabayashi KI, et a1. Swimming stress in DN14-3-3 mice triggers maladaptive cardiac remodeling: role of p38 MAPK [J]. Am J Physiol Heart Circ Physiol, 2007,292(3):H1269-1277.
[8] Miller MK, Bang ML, Witt CC, et a1. The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules [J]. J Mol Biol, 2003, 333(5):951-964.
[9] W. Glen Pyle R, John S. At the crossroads of myocardial signaling: the role of Z-Discs in intracellular signaling and cardiac function [J]. Circ. Res, 2004, 94: 296-305.
[10] Michael G, Robert EH, Norbert H, et a1. Conditional expression of mutant M-line Titins results in cardiomyopathy with altered sarcomere structure [J]. Biological Chemistry, 2003, 278: 6059-6065.
[11] Aihara Y, Kurabayashi M, Saito Y, et a1. Cardiac ankyrin repeat protein is a novel marker of cardiac hypertrophy: Role of M-CAT element within the promoter [J]. Hypertension, 2000, 36(1): 48-53.
[12] Alan RC, Janet S, Wang W, et a1. Osteopontin modulates angiotensin II induced fibrosis in the intact murine heart [J]. J. Am. Coll. Cardiol, 2004, 43:1698-1705.
[13] Andree B, Lusebrink J, Kohrer K, et a1. Switch from actin alpha1 to alpha2 expression and upregulation of biomarkers for pressure overload and cardiac hypertrophy in taurine-deficient mouse heart [J]. Biol Chem, 2006, 387 (10-11): 1449-1454.
[14] Jeffrey GW, Caroline O, Thomas HH. Physiologic cardiac hypertrophy during pregnancy involves a change in gene expression regulating cardiac metabolism [J]. FASEB, 2006, 20:A1188.
[15] Han XJ, Chae JK, Lee MJ, et a1. Involvement of GADD153 and cardiac ankyrin repeat protein in hypoxia-induced apoptosis of H9c2 cells [J]. Biological Chemistry, 2005, 280(24): 23122–23129.
[16] Auersachs J, Galuppo P, Fraccarollo D, et a1.Improvement of left ventricular remodeling and function by hydroxymethylglutaryl coenzyme a reductase inhibition with cerivastatin in rats with heart failure after myocardial infarction [J].Circulation,2001, 104(9): 982-985.
[17] Zhang JY, Cheng X, Liao YH, et a1. Simvastatin regulates myocardial cytokine expression and improves ventricular remodeling in rats after acute myocardial infarction [J]. Cardiovascular Drugs & Therapy, 2005, 19(1): 13-21.
[18] Chen JC, Huang KC, Lin WW. HMG-CoA reductase inhibitors upregulate heme oxygenase-1 expression in murine RAW264.7 macrophages via ERK, p38 MAPK and protein kinase G pathways [J]. Cell Signal, 2006, 18(1):32-39.
[19] Efthymiou CA, Mocanu MM, Yellon DM, et al. Atorvastatin and myocardial reperfusion injury: new pleiotropic effect implicating multiple prosurvival signaling [J]. Cardiovasc Pharmacol, 2005, 45(3):247-252.
[20] 覃数,陈运贞.大白鼠实验性心肌缺血再灌注模型制备与心电图改变的特点[J].重庆医科大学学报,1998;23:8-11.
[21] Izumiya Y, Kim S, Izumi Y, et al. Apoptosis signal-regulating kinase 1 plays a pivotal role in angiotensin II-induced cardiac hypertrophy and remodeling [J]. Circ Res, 2003, 93: 874?883.
[22] Qin F, Liang MC, Liang CS. Progressive left ventricular remodeling, myocyte apoptosis, and protein signaling cascades after myocardial infarction in rabbits [J]. Biochim Biophys Acta, 2005, 1740(3): 499-513.
[23] Madoka M, Yoshihito T, Takeshi A, et al. Activation of TGF-β1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats [J]. Am J Physiol Heart Circ Physiol, 2006, 290: H709-H715.
[24] See F, Thomas W, Way K, et al. p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat [J]. J Am Coll Cardiol. 2004, 44(8):1679-1689.
[25] Stuart AC, Takashi M, Ling L, et a1. Transcriptional effects of chronic Akt activation in the heart [J]. Biological Chemistry, 2002, 277(25): 22528-22533.
[1] Hirotani S, Otsu K, Nishida K,et a1. Involvement of Nuclear Factor-[κ]B and Apoptosis Signal-Regulating kinase 1 in G-Protein-Coupled Receptor Agonist- Induced Cardiomyocyte Hypertrophy [J]. Circulation,2002,105(4): 509-515.
[2] Tenhunen O,Rys? J,Ilves M, et a1. Identification of Cell Cycle Regulatory and Inflammatory Genes As Predominant Targets of p38 Mitogen-Activated Protein Kinase in the Heart [J]. Circulation Research , 2006 99(5):485-493.
[3] 魏倩萍, 邓华聪, 赵 劫. P38MAPK 信号通路在大鼠肾小球系膜细胞表达VEGF 中的作用 [J] .重庆医学,2005, 34 (1):16-18.
[4] Tyler ZARUBIN, Jiahuai HAN. Activation and signaling of the p38 MAP kinase pathway [J]. Cell Research, 2005, 15(1):11-18.
[5] Rebecca H Ritchie, Lea MD Delbridge. Cardiac hypertrophy, substrate utilization and metabolic remodeling: cause or effect? [J] Clinical and Experimental Pharmacology and Physiology, 2006, 33(1-2):159–166.
[6] Tsujimoto I, Hikoso S, Yamaguchi O, et a1. The Antioxidant Edaravone Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy [J]. Hypertension,2005, 45(5): 921-926.
[7] Cheng TH, Shih NL, Chen CH, et a1. Role of mitogen-activated protein kinase pathway in reactive oxygen species-mediated endothelin-1-induced β-myosin heavy chain gene expression and cardiomyocyte hypertrophy [J]. J Biomed Sci,2005, 12(1):123-133.
[8] Yasuhiro I, Shokei K, Yasukatsu I, et a1. Apoptosis Signal-Regulating Kinase 1 Plays a Pivotal Role in Angiotensin II-Induced Cardiac Hypertrophy and Remodeling [J]. Circulation Research, 2003, 93(9): 874-883.
[9] Braz JC, Bueno OF, Liang Q, et a1. Targeted inhibition of p38MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling [J]. J Clin Invest, 2003,111(10): 1475-1486.
[10] Pu L, Dimitrios G, Attila K. The in vivo role of p38MAP kinases in cardiac remodeling and restrictive cardiomyopathy [J]. Proc Natl Acad Sci U S A, 2001, 98(21): 12283-12288.
[11] Prakash P, Watanabe K, Hirabayashi KI, et a1. Swimming stress in DN14-3-3 mice triggers maladaptive cardiac remodeling: role of p38 MAPK [J]. Am J PhysiolHeart Circ Physiol, 2007, 292(3):H1269-1277.
[12] Onan D, Pipolo L, Yang E, et a1. Urotensin II Promotes Hypertrophy of Cardiac Myocytes via Mitogen-Activated Protein Kinases [J]. Mol Endocrinol, 2004, 18(9): 2344 –2354.
[13] Tu VC, Bahl JJ, Chen QM. Distinct roles of p42/p44(ERK)and p38MAPK in oxidant-induced AP-1 activation and cardiomyocyte hypertrophy [J]. Cardiovasc Toxicol, 2003,3(2): 119-133.
[14] Tsoporis JN, Marks A, Haddad A, et a1. S100B Expression Modulates Left Ventricular Remodeling After Myocardial Infarction in Mice [J]. Circulation, 2005, 111(5): 598-606.
[15] Yoko IT, Takashi M, Yoshitoshi K a1. Activation of Peroxisome Proliferator -activated Receptor-α? Decreases Endothelin-1-induced p38 Mitogen-activated Protein Kinase Activation in Cardiomyocytes [J] . J Cardiovasc Pharmacol , 2004, 44(suppl 1): S358–S361.
[16] Aihara Y, Kurabayashi M, Saito Y, et a1. Cardiac Ankyrin Repeat Protein Is a Novel Marker of Cardiac Hypertrophy: Role of M-CAT Element Within the Promoter [J]. Hypertension, 2000, 36(1): 48-53.
[17] Zhang D, Gaussin V, Taffet GE, et a1. TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice [J]. Nat Med, 2000, 6(5): 556-563.
[18] Matsumoto-Ida M, Takimoto Y, Aoyama T,et a1. Activation of TGF-β1-TAK1- p38MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats [J]. Am J Physiol Heart Circ Physiol, 2006, 290(2): 709-715.
[19] See F, Thomas W, Way K, et a1. p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat[J]. J Am Coll Cardiol,2004,44(8):1679-1689.
[2] becca HR, Lea MD. Cardiac hypertrophy, substrate utilization and metabolic remodeling: cause or effect [J]? Clinical and Experimental Pharmacology and Physiology, 2006, 33(1-2):159–166.
[3] Cheng TH, Shih NL, Chen CH, et a1. Role of mitogen-activated protein kinase pathway in reactive oxygen species-mediated endothelin-1-induced β-myosin heavy chain gene expression and cardiomyocyte hypertrophy [J]. J Biomed Sci, 2005, 12(1): 123-133.
[4] Tsujimoto I, Hikoso S, Yamaguchi O, et a1. The antioxidant edaravone attenuates pressure overload-induced left ventricular hypertrophy [J]. Hypertension,2005,45(5): 921-926.
[5] Zhang D, Gaussin V, Taffet GE, et a1. TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice [J]. Nat Med,2000,6(5):556-563.
[6] Yoko IT, Takashi M, Yoshitoshi K,et a1. Activation of peroxisome proliferator- activated receptor-α? decreases endothelin-1-induced p38 mitogen-activated protein kinase activation in cardiomyocytes [J]. J Cardiovasc Pharmacol, 2004, 44(suppl 1) : S358–S361.
[7] Prakash P, Watanabe K, Hirabayashi KI, et a1. Swimming stress in DN14-3-3 mice triggers maladaptive cardiac remodeling: role of p38 MAPK [J]. Am J Physiol Heart Circ Physiol, 2007,292(3):H1269-1277.
[8] Miller MK, Bang ML, Witt CC, et a1. The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules [J]. J Mol Biol, 2003, 333(5):951-964.
[9] W. Glen Pyle R, John S. At the crossroads of myocardial signaling: the role of Z-Discs in intracellular signaling and cardiac function [J]. Circ. Res, 2004, 94: 296-305.
[10] Michael G, Robert EH, Norbert H, et a1. Conditional expression of mutant M-line Titins results in cardiomyopathy with altered sarcomere structure [J]. Biological Chemistry, 2003, 278: 6059-6065.
[11] Aihara Y, Kurabayashi M, Saito Y, et a1. Cardiac ankyrin repeat protein is a novel marker of cardiac hypertrophy: Role of M-CAT element within the promoter [J]. Hypertension, 2000, 36(1): 48-53.
[12] Alan RC, Janet S, Wang W, et a1. Osteopontin modulates angiotensin II induced fibrosis in the intact murine heart [J]. J. Am. Coll. Cardiol, 2004, 43:1698-1705.
[13] Andree B, Lusebrink J, Kohrer K, et a1. Switch from actin alpha1 to alpha2 expression and upregulation of biomarkers for pressure overload and cardiac hypertrophy in taurine-deficient mouse heart [J]. Biol Chem, 2006, 387 (10-11): 1449-1454.
[14] Jeffrey GW, Caroline O, Thomas HH. Physiologic cardiac hypertrophy during pregnancy involves a change in gene expression regulating cardiac metabolism [J]. FASEB, 2006, 20:A1188.
[15] Han XJ, Chae JK, Lee MJ, et a1. Involvement of GADD153 and cardiac ankyrin repeat protein in hypoxia-induced apoptosis of H9c2 cells [J]. Biological Chemistry, 2005, 280(24): 23122–23129.
[16] Auersachs J, Galuppo P, Fraccarollo D, et a1.Improvement of left ventricular remodeling and function by hydroxymethylglutaryl coenzyme a reductase inhibition with cerivastatin in rats with heart failure after myocardial infarction [J].Circulation,2001, 104(9): 982-985.
[17] Zhang JY, Cheng X, Liao YH, et a1. Simvastatin regulates myocardial cytokine expression and improves ventricular remodeling in rats after acute myocardial infarction [J]. Cardiovascular Drugs & Therapy, 2005, 19(1): 13-21.
[18] Chen JC, Huang KC, Lin WW. HMG-CoA reductase inhibitors upregulate heme oxygenase-1 expression in murine RAW264.7 macrophages via ERK, p38 MAPK and protein kinase G pathways [J]. Cell Signal, 2006, 18(1):32-39.
[19] Efthymiou CA, Mocanu MM, Yellon DM, et al. Atorvastatin and myocardial reperfusion injury: new pleiotropic effect implicating multiple prosurvival signaling [J]. Cardiovasc Pharmacol, 2005, 45(3):247-252.
[20] 覃数,陈运贞.大白鼠实验性心肌缺血再灌注模型制备与心电图改变的特点[J].重庆医科大学学报,1998;23:8-11.
[21] Izumiya Y, Kim S, Izumi Y, et al. Apoptosis signal-regulating kinase 1 plays a pivotal role in angiotensin II-induced cardiac hypertrophy and remodeling [J]. Circ Res, 2003, 93: 874?883.
[22] Qin F, Liang MC, Liang CS. Progressive left ventricular remodeling, myocyte apoptosis, and protein signaling cascades after myocardial infarction in rabbits [J]. Biochim Biophys Acta, 2005, 1740(3): 499-513.
[23] Madoka M, Yoshihito T, Takeshi A, et al. Activation of TGF-β1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats [J]. Am J Physiol Heart Circ Physiol, 2006, 290: H709-H715.
[24] See F, Thomas W, Way K, et al. p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat [J]. J Am Coll Cardiol. 2004, 44(8):1679-1689.
[25] Stuart AC, Takashi M, Ling L, et a1. Transcriptional effects of chronic Akt activation in the heart [J]. Biological Chemistry, 2002, 277(25): 22528-22533.
[1] Hirotani S, Otsu K, Nishida K,et a1. Involvement of Nuclear Factor-[κ]B and Apoptosis Signal-Regulating kinase 1 in G-Protein-Coupled Receptor Agonist- Induced Cardiomyocyte Hypertrophy [J]. Circulation,2002,105(4): 509-515.
[2] Tenhunen O,Rys? J,Ilves M, et a1. Identification of Cell Cycle Regulatory and Inflammatory Genes As Predominant Targets of p38 Mitogen-Activated Protein Kinase in the Heart [J]. Circulation Research , 2006 99(5):485-493.
[3] 魏倩萍, 邓华聪, 赵 劫. P38MAPK 信号通路在大鼠肾小球系膜细胞表达VEGF 中的作用 [J] .重庆医学,2005, 34 (1):16-18.
[4] Tyler ZARUBIN, Jiahuai HAN. Activation and signaling of the p38 MAP kinase pathway [J]. Cell Research, 2005, 15(1):11-18.
[5] Rebecca H Ritchie, Lea MD Delbridge. Cardiac hypertrophy, substrate utilization and metabolic remodeling: cause or effect? [J] Clinical and Experimental Pharmacology and Physiology, 2006, 33(1-2):159–166.
[6] Tsujimoto I, Hikoso S, Yamaguchi O, et a1. The Antioxidant Edaravone Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy [J]. Hypertension,2005, 45(5): 921-926.
[7] Cheng TH, Shih NL, Chen CH, et a1. Role of mitogen-activated protein kinase pathway in reactive oxygen species-mediated endothelin-1-induced β-myosin heavy chain gene expression and cardiomyocyte hypertrophy [J]. J Biomed Sci,2005, 12(1):123-133.
[8] Yasuhiro I, Shokei K, Yasukatsu I, et a1. Apoptosis Signal-Regulating Kinase 1 Plays a Pivotal Role in Angiotensin II-Induced Cardiac Hypertrophy and Remodeling [J]. Circulation Research, 2003, 93(9): 874-883.
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