NADPH氧化酶在心梗后大鼠心室肌中的改变及其干预研究
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摘要
目的:探讨心梗后大鼠左室心肌组织中NADPH氧化酶的变化及夹竹桃麻素对NADPH氧化酶干预作用的机制。
方法:取雄性SD大鼠,通过结扎左冠状动脉前降支建立大鼠心肌梗塞模型,假手术组为无创缝线只穿过前降支而不结扎,将两组再随机分为药物干预组和安慰剂组两个亚组,术后第二天分别给予等体积的夹竹桃麻素溶液(15mg/kg/day)和生理盐水灌胃,共五周。分别于术前和术后第六周行心超检查。术后第六周处死大鼠,取出心脏,用左心室非梗塞区心肌组织制备心肌匀浆液,采用吸收光度法测定非梗塞区心肌组织中O2-浓度和NADPH氧化酶活性,采用RT-PCR法测定心室肌组织中NADPH氧化酶亚单位gp91phoxmRNA的表达水平,并观察心室肌组织中O2-浓度与NADPH氧化酶活性和gp91phoxmRNA表达水平的相关性。
结果:1.假手术组大鼠心室肌组织中O2-浓度为(50300±3416)RLU/mg蛋白,心梗组O2-浓度为(83200±7582)RLU/mg蛋白,与假手术组相比有显著统计学差异(P<0.01)。心梗药物干预组O2-浓度为(53300±5517)RLU/mg蛋白,与心梗组相比具有统计学差异(P<0.05),但与假手术组相比无统计学差异(P=0.45)。假手术药物干预组O2-浓度为(47100±2126)RLU/mg蛋白,与假手术组相比无统计学差异(P=0.41)。
2.假手术组大鼠心室肌组织中NADPH氧化酶活性为(3.38±0.35)RLU/mg蛋白,心梗组NADPH氧化酶活性为(4.77±0.46)RLU/mg蛋白,与假手术组相比有显著统计学差异(P<0.01)。心梗药物干预组NADPH氧化酶活性为(3.62±0.32)RLU/mg蛋白,与心梗组相比具有统计学差异(P<0.05),但与假手术组相比无统计学差异(P=0.27)。假手术药物干预组NADPH氧化酶活性为(3.19±0.32)RLU/mg蛋白,与假手术组相比无统计学差异(P=0.37)。
3.假手术组大鼠心室肌组织中NADPH氧化酶亚单位gp91phoxmRNA表达水平为(0.46±0.07),心梗组gp91phoxmRNA的表达水平为(0.69±0.06),与假手术组相比有显著统计学差异(P<0.01)。心梗药物干预组gp91phoxmRNA的表达水平为(0.49±0.06),与心梗组相比具有统计学差异(P<0.05),与假手术组相比无统计学差异(P=0.54)。假手术药物干预组gp91phoxmRNA表达水平为(0.44±0.03),与假手术组相比无统计学差异(P=0.64)。
4.心室肌组织中O2-浓度与NADPH氧化酶活性有显著相关性(R=0.73,P<0.01),与NADPH氧化酶亚单位gp91phoxmRNA表达水平有显著相关性(R=0.80,P<0.01)。
结论:1.心梗组大鼠心室肌组织中O2-浓度、NADPH氧化酶活性和gp91phoxmRNA表达水平明显增高,NADPH氧化酶活性和gp91phoxmRNA表达水平与O2-浓度升高水平呈显著相关,表明心梗后NADPH氧化酶系统被激活。
2.夹竹桃麻素通过显著抑制NADPH氧化酶活性和gp91phoxmRNA表达减少O2-生成,提示夹竹桃麻素作为NADPPH氧化酶抑制剂可显著减轻心梗后心肌组织氧化应激水平。
Objective: To explore the changes of NADPH oxidase in the rat ventricular tissue after myocardial infarction, and the intervention study on the NADPH oxidase with apocynin.
Methods: Using male SD rats, MI group was made by ligation of anterior descending coronary artery, the sham group underwent the same procedure without coronary artery ligation, the animals with MI or sham group were assigned randomly to intragastrically receive apocynin (15 mg/kg/day) or saline respectively on the second day after operation for 5 weeks. Echocardiogram were used before the operation and on the 6th week after the operation respectively. On the 6th week after the operation, the rats were killed and the hearts were removed. The concentration of O2- and the activity of NADPH oxidase were measured by the method of absorption photometry, and the expression level of gp91phox mRNA was detected with RT-PCR, and the correlations between the concentration of O2- and the activity of the NADPH oxidase, and the expression level of the gp91phox mRNA were respectively calculated.
Results:1. The concentration of O2- in the MI group[(83200±7582)RLU/mg protein] increased significantly compared to the sham group [(50300±3416)RLU/mg protein](P<0.01). The concentration of O2- in the MI+apocynin group[(53300±5517)RLU/mg protein] decreased significantly compared to the MI group(P<0.05). There were no significant differences between the MI+apocynin group, the sham+apocynin group and the sham group (P=0.45, 0.41).
2. The activity of NADPH oxidase in the MI group [(4.77±0.46)RLU/mg protein] increased significantly compared to the sham group[(3.38±0.35)RLU/mg protein](P<0.01). The activity of the NADPH oxidase in the MI+apocynin group[(3.62±0.32)RLU/mg protein] decreased significantly compared to the MI group(P<0.05). There were no significant differences between the MI+apocynin group, the sham+apocynin group and the sham group(P= 0.27, 0.37).
3. The expression level of gp91phox mRNA in the MI group [0.69±0.06]increased significantly compared to the sham group[0.46±0.07](P<0.01). The expression level of gp91phox mRNA in the MI+apocynin group[0.49±0.06] decreased significantly compared to the MI group(P<0.05). There were no significant differences between the MI+apocynin group, the sham+apocynin group and the sham group(P=0.54, 0.64).
4. The concentration of O2- positively correlated to the activity of the NADPH oxidase(R=0.73,P<0.01), and the expression level of the gp91phox mRNA(R=0.80,P<0.01).
Conclusions: 1. The concentration of O2-, the activity of the NADPH oxidase and the expression level of gp91phox mRNA in the MI group increase significantly. There are positive correlations between the concentration of O2- and the activity of NADPH oxidase, and between the concentration of O2- and the expression level of gp91phox mRNA. These indicate that the NADPH oxidase system is actived after myocardial infarction.
2. The apocynin decreases the production of O2- by inhibiting the activity of NADPH oxidase and the expression level of gp91phox mRNA. This suggests that apocynin as a NADPH oxidase inhibitor could significantly attenuate the level of oxidase stress after myocardial infarction.
方法:取雄性SD大鼠,通过结扎左冠状动脉前降支建立大鼠心肌梗塞模型,假手术组为无创缝线只穿过前降支而不结扎,将两组再随机分为药物干预组和安慰剂组两个亚组,术后第二天分别给予等体积的夹竹桃麻素溶液(15mg/kg/day)和生理盐水灌胃,共五周。分别于术前和术后第六周行心超检查。术后第六周处死大鼠,取出心脏,用左心室非梗塞区心肌组织制备心肌匀浆液,采用吸收光度法测定非梗塞区心肌组织中O2-浓度和NADPH氧化酶活性,采用RT-PCR法测定心室肌组织中NADPH氧化酶亚单位gp91phoxmRNA的表达水平,并观察心室肌组织中O2-浓度与NADPH氧化酶活性和gp91phoxmRNA表达水平的相关性。
结果:1.假手术组大鼠心室肌组织中O2-浓度为(50300±3416)RLU/mg蛋白,心梗组O2-浓度为(83200±7582)RLU/mg蛋白,与假手术组相比有显著统计学差异(P<0.01)。心梗药物干预组O2-浓度为(53300±5517)RLU/mg蛋白,与心梗组相比具有统计学差异(P<0.05),但与假手术组相比无统计学差异(P=0.45)。假手术药物干预组O2-浓度为(47100±2126)RLU/mg蛋白,与假手术组相比无统计学差异(P=0.41)。
2.假手术组大鼠心室肌组织中NADPH氧化酶活性为(3.38±0.35)RLU/mg蛋白,心梗组NADPH氧化酶活性为(4.77±0.46)RLU/mg蛋白,与假手术组相比有显著统计学差异(P<0.01)。心梗药物干预组NADPH氧化酶活性为(3.62±0.32)RLU/mg蛋白,与心梗组相比具有统计学差异(P<0.05),但与假手术组相比无统计学差异(P=0.27)。假手术药物干预组NADPH氧化酶活性为(3.19±0.32)RLU/mg蛋白,与假手术组相比无统计学差异(P=0.37)。
3.假手术组大鼠心室肌组织中NADPH氧化酶亚单位gp91phoxmRNA表达水平为(0.46±0.07),心梗组gp91phoxmRNA的表达水平为(0.69±0.06),与假手术组相比有显著统计学差异(P<0.01)。心梗药物干预组gp91phoxmRNA的表达水平为(0.49±0.06),与心梗组相比具有统计学差异(P<0.05),与假手术组相比无统计学差异(P=0.54)。假手术药物干预组gp91phoxmRNA表达水平为(0.44±0.03),与假手术组相比无统计学差异(P=0.64)。
4.心室肌组织中O2-浓度与NADPH氧化酶活性有显著相关性(R=0.73,P<0.01),与NADPH氧化酶亚单位gp91phoxmRNA表达水平有显著相关性(R=0.80,P<0.01)。
结论:1.心梗组大鼠心室肌组织中O2-浓度、NADPH氧化酶活性和gp91phoxmRNA表达水平明显增高,NADPH氧化酶活性和gp91phoxmRNA表达水平与O2-浓度升高水平呈显著相关,表明心梗后NADPH氧化酶系统被激活。
2.夹竹桃麻素通过显著抑制NADPH氧化酶活性和gp91phoxmRNA表达减少O2-生成,提示夹竹桃麻素作为NADPPH氧化酶抑制剂可显著减轻心梗后心肌组织氧化应激水平。
Objective: To explore the changes of NADPH oxidase in the rat ventricular tissue after myocardial infarction, and the intervention study on the NADPH oxidase with apocynin.
Methods: Using male SD rats, MI group was made by ligation of anterior descending coronary artery, the sham group underwent the same procedure without coronary artery ligation, the animals with MI or sham group were assigned randomly to intragastrically receive apocynin (15 mg/kg/day) or saline respectively on the second day after operation for 5 weeks. Echocardiogram were used before the operation and on the 6th week after the operation respectively. On the 6th week after the operation, the rats were killed and the hearts were removed. The concentration of O2- and the activity of NADPH oxidase were measured by the method of absorption photometry, and the expression level of gp91phox mRNA was detected with RT-PCR, and the correlations between the concentration of O2- and the activity of the NADPH oxidase, and the expression level of the gp91phox mRNA were respectively calculated.
Results:1. The concentration of O2- in the MI group[(83200±7582)RLU/mg protein] increased significantly compared to the sham group [(50300±3416)RLU/mg protein](P<0.01). The concentration of O2- in the MI+apocynin group[(53300±5517)RLU/mg protein] decreased significantly compared to the MI group(P<0.05). There were no significant differences between the MI+apocynin group, the sham+apocynin group and the sham group (P=0.45, 0.41).
2. The activity of NADPH oxidase in the MI group [(4.77±0.46)RLU/mg protein] increased significantly compared to the sham group[(3.38±0.35)RLU/mg protein](P<0.01). The activity of the NADPH oxidase in the MI+apocynin group[(3.62±0.32)RLU/mg protein] decreased significantly compared to the MI group(P<0.05). There were no significant differences between the MI+apocynin group, the sham+apocynin group and the sham group(P= 0.27, 0.37).
3. The expression level of gp91phox mRNA in the MI group [0.69±0.06]increased significantly compared to the sham group[0.46±0.07](P<0.01). The expression level of gp91phox mRNA in the MI+apocynin group[0.49±0.06] decreased significantly compared to the MI group(P<0.05). There were no significant differences between the MI+apocynin group, the sham+apocynin group and the sham group(P=0.54, 0.64).
4. The concentration of O2- positively correlated to the activity of the NADPH oxidase(R=0.73,P<0.01), and the expression level of the gp91phox mRNA(R=0.80,P<0.01).
Conclusions: 1. The concentration of O2-, the activity of the NADPH oxidase and the expression level of gp91phox mRNA in the MI group increase significantly. There are positive correlations between the concentration of O2- and the activity of NADPH oxidase, and between the concentration of O2- and the expression level of gp91phox mRNA. These indicate that the NADPH oxidase system is actived after myocardial infarction.
2. The apocynin decreases the production of O2- by inhibiting the activity of NADPH oxidase and the expression level of gp91phox mRNA. This suggests that apocynin as a NADPH oxidase inhibitor could significantly attenuate the level of oxidase stress after myocardial infarction.
引文
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[15] Doussiere J, Gaillard J, Vignais P V. Electron transfer across the O2- generating ?avocytochrome b of neutrophils: evidence for a transition from a low-spin state to a high-spin state of the heme iron component [J]. Bio chemistry,1999; 35:13400–13410.
[16] Isogai Y, Iizuka T, Shiro Y. The mechanism of electron donation to molecular oxygen by phagocytic cytochrome b558 [J]. Biol Chem, 1995; 270:7853-7857.
[17] Huang J, Hitt N D, Kleinberg M E. Stoichiometry of p22phox and gp91phox in phagocyte cytochrome b588 [J]. Biochemistry, 1995; 34:16753 -16757.
[18] Leto T L, Adams A G, de Mendez I. Assembly of the phagocyte NADPH oxidase: binding of Src homology 3 domains to proline-rich targets[J]. Proc Natl Acad Sci, 1994; 91:10650–10654.
[19] Gorzalczany Y, Sigal N, Itan M,et al. Targeting of Rac1 to the phagocyte membrane is sufficient for the induction of NADPH oxidase assembly[J]. Biol Chem, 2000; 275:40073–40081.
[20] Welch HC, Coadwell WJ, Ellson CD, et al.P-Rex1,a PtdIns (3,4, 5)P3- and Gαγ-regulated guanine-nucleotide exchange factor for Rac[J]. Cell, 2002;108:809-821.
[21] Price M O, Atkinson S J, Knaus U G, et al. Rac activation induces NADPH oxidase activity in transgenic COSphox cells,and the level of superoxide production is exchange factor-dependent [J]. Biol Chem, 2002; 277:19220-19228.
[22] Kanai F, Liu H, Field S J, et al.The PX domains of p47phox and p40phox bind to lipid products of PI(3)K [J]. Nat Cell Biol, 2001; 3:675 -678.
[23] Zhan Y, He D, Newburger P E, et al.p47phox PX domain of NADPH oxidase targets cell membrane via moesin-mediated association with the actin cytoskeleton[J]. Cell Biochem, 2004; 92:795-809.
[24] Nauseef W M. Assembly of the phagocyte NADPH oxidase[J]. Histochem Cell Biol, 2004; 122:277–291.
[25] Fontayne A, Dang P M, Gougerot-Pocidalo M A, et al.Phosphorylation of p47phox sites by PKCα,βⅡ,γ,δ:effect on binding to p22phox and on NADPH oxidase activation[J]. Biochemistry, 2002; 41:7743-7750.
[26] Dewas C, Fay M, Gougerot-Pocidalo M A, et al.The mitogen -activated protein kinase extracellular signal-regulated kinase 1/2 pathway is involved in formyl-methionyl– leucyl–phenylala nine-induced p47phox phosphorylation in human Neutrophils [J]. Immunol, 2000; 165:5238-5244.
[27] Knaus U G, Morris S, Dong H J, et al. Regulation of human leukocyte p21-activated kinases through G protein-coupled receptors[J]. Science, 1995; 269:221-223.
[28] Park H S, Lee S M, Lee J H, et al. Phosphorylation of the leu- cocyte NADPH oxidase subunit p47phox by casein kinase 2: conformation-dependent phosphory- lation and modulation of oxidase activity[J]. Biochem, 2001; 358:783-790.
[29] Hoyal C R, Gutierrez A, Young B M, et al. Modulation of p47phox activity by site-specific phosphorylation:Akt-dependent activation of the NADPH oxidase[J]. Proc Natl Acad Sci, 2003; 100:5130–5135.
[30] Nauseef WM, Volpp BD, McCormick S, et al. Assembly of the neutrophil respiratory burst oxidase: protein kinase C promotes cytoskeletal and membrane association of cytosolic oxidase components[J]. Biol Chem, 1991; 266:5911-5917.
[31] Koga H, Terasawa H, Nunoi H, et al. Tetratricopeptide repeat (TPR) motifs of p67phox participate in interaction with the small GTPase Rac and activation of the phagocyte NADPH oxidase [J]. Biol Chem, 1999; 274:25051–25060.
[32] Freeman J L, Lambeth J D. NADPH oxidase activity is independent of p47phox in vitro [J]. Biol Chem, 1996; 271:22578- 22582.
[33] Gorzalczany Y, Alloul N, Sigal N, etal. A prenylated p67phox-Rac1 chimera elicits NADPH-dependent superoxide production by phagocyte membranes in the absence of an activator and of p47phox:conversion of a pagan NADPH oxidase to monotheism [J]. Biol Chem, 2002; 277:18605-18610.
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[1] Kanfmann JA, Bickford PC, Taglialatela G. Free redical -dependent change in constitutive nuclear factor kappaβin the aged hippocampus[J]. Neuroreport, 2003; 13(15):1917-1928.
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[12] Babior BM. The respiratory burst oxidase[J]. Curr Opin Hematol, 1995; 2(1):55-60.
[13] Lambeth JD, Cheng G,Arnold RS, et a1. Novel homologs of gp91phox [J]. Trends Biochem Sci, 2000;25(10):459-461.
[14] Cross A R, Erickson R W, Curnutte J T. Simultaneous presence of p47phox and ?avocytochrome b-245 are required for the activation of NADPH oxidase by anionic amphiphiles: evidence for an intermediate state of oxidase activation [J]. Biol Chem, 1999, 274:15519-15525.
[15] Doussiere J, Gaillard J, Vignais P V. Electron transfer across the O2- generating ?avocytochrome b of neutrophils: evidence for a transition from a low-spin state to a high-spin state of the heme iron component [J]. Bio chemistry,1999; 35:13400–13410.
[16] Isogai Y, Iizuka T, Shiro Y. The mechanism of electron donation to molecular oxygen by phagocytic cytochrome b558 [J]. Biol Chem, 1995; 270:7853-7857.
[17] Huang J, Hitt N D, Kleinberg M E. Stoichiometry of p22phox and gp91phox in phagocyte cytochrome b588 [J]. Biochemistry, 1995; 34:16753 -16757.
[18] Leto T L, Adams A G, de Mendez I. Assembly of the phagocyte NADPH oxidase: binding of Src homology 3 domains to proline-rich targets[J]. Proc Natl Acad Sci, 1994; 91:10650–10654.
[19] Gorzalczany Y, Sigal N, Itan M,et al. Targeting of Rac1 to the phagocyte membrane is sufficient for the induction of NADPH oxidase assembly[J]. Biol Chem, 2000; 275:40073–40081.
[20] Welch HC, Coadwell WJ, Ellson CD, et al.P-Rex1,a PtdIns (3,4, 5)P3- and Gαγ-regulated guanine-nucleotide exchange factor for Rac[J]. Cell, 2002;108:809-821.
[21] Price M O, Atkinson S J, Knaus U G, et al. Rac activation induces NADPH oxidase activity in transgenic COSphox cells,and the level of superoxide production is exchange factor-dependent [J]. Biol Chem, 2002; 277:19220-19228.
[22] Kanai F, Liu H, Field S J, et al.The PX domains of p47phox and p40phox bind to lipid products of PI(3)K [J]. Nat Cell Biol, 2001; 3:675 -678.
[23] Zhan Y, He D, Newburger P E, et al.p47phox PX domain of NADPH oxidase targets cell membrane via moesin-mediated association with the actin cytoskeleton[J]. Cell Biochem, 2004; 92:795-809.
[24] Nauseef W M. Assembly of the phagocyte NADPH oxidase[J]. Histochem Cell Biol, 2004; 122:277–291.
[25] Fontayne A, Dang P M, Gougerot-Pocidalo M A, et al.Phosphorylation of p47phox sites by PKCα,βⅡ,γ,δ:effect on binding to p22phox and on NADPH oxidase activation[J]. Biochemistry, 2002; 41:7743-7750.
[26] Dewas C, Fay M, Gougerot-Pocidalo M A, et al.The mitogen -activated protein kinase extracellular signal-regulated kinase 1/2 pathway is involved in formyl-methionyl– leucyl–phenylala nine-induced p47phox phosphorylation in human Neutrophils [J]. Immunol, 2000; 165:5238-5244.
[27] Knaus U G, Morris S, Dong H J, et al. Regulation of human leukocyte p21-activated kinases through G protein-coupled receptors[J]. Science, 1995; 269:221-223.
[28] Park H S, Lee S M, Lee J H, et al. Phosphorylation of the leu- cocyte NADPH oxidase subunit p47phox by casein kinase 2: conformation-dependent phosphory- lation and modulation of oxidase activity[J]. Biochem, 2001; 358:783-790.
[29] Hoyal C R, Gutierrez A, Young B M, et al. Modulation of p47phox activity by site-specific phosphorylation:Akt-dependent activation of the NADPH oxidase[J]. Proc Natl Acad Sci, 2003; 100:5130–5135.
[30] Nauseef WM, Volpp BD, McCormick S, et al. Assembly of the neutrophil respiratory burst oxidase: protein kinase C promotes cytoskeletal and membrane association of cytosolic oxidase components[J]. Biol Chem, 1991; 266:5911-5917.
[31] Koga H, Terasawa H, Nunoi H, et al. Tetratricopeptide repeat (TPR) motifs of p67phox participate in interaction with the small GTPase Rac and activation of the phagocyte NADPH oxidase [J]. Biol Chem, 1999; 274:25051–25060.
[32] Freeman J L, Lambeth J D. NADPH oxidase activity is independent of p47phox in vitro [J]. Biol Chem, 1996; 271:22578- 22582.
[33] Gorzalczany Y, Alloul N, Sigal N, etal. A prenylated p67phox-Rac1 chimera elicits NADPH-dependent superoxide production by phagocyte membranes in the absence of an activator and of p47phox:conversion of a pagan NADPH oxidase to monotheism [J]. Biol Chem, 2002; 277:18605-18610.
[34] Diebold B A, Bokoch G M. Molecular basis for Rac2 regulation of phagocyte NADPH oxidase[J]. Nat Immunol, 2001; 2:211-215.
[35] Dang P M, Babior B M, Smith R M. NADPH dehydrogenase activity of p67phox,a cytosolic subunit of the leukocyte NADPH oxidase[J]. Biochemistry, 1999; 38: 5746-5753.
[36] Kuribayashi F, Nunoi H, Wakamatsu Tsunawaki, et al.The adaptor protein p40phox as a positive regulator of the superoxide-producing phagocyte oxidase[J]. EMBO, 2002; 21:6312- 6320.
[37] Fuchs A, Dagher MC, Vignais PV. Mapping the domains of interaction of p40phox with both p47phox and p67phox of the neutrophil oxidase complex using the two-hybrid system [J]. Biol Chem, 1995; 270:5695-5697.
[38] Han CH, Freeman JL, Lee T, et al. Regulation of the neutrophil respiratory burst oxidase:identification of an ac- tivation domain in p67phox[J]. Biol Chem, 1998, 273: 16663-16668.
[39] Han CH,Lee MH. Activation domain in p67phox regulates the steady state reduction of FAD in gp91phox [J]. Vet Sci, 2000; 1:27-31.
[40] Grizot S, Grandvaux N, Fieschi F, et al. Small angle neutron scattering and gel filtration analyses of neutrophil NADPH oxidase cytosolic factors highlight the role of the C-terminal end of p47phox in the association with p40phox[J]. Biochemis- try, 2001; 40:3127-3133.
[41] Ellson CD,Gobert-Gosse S, Anderson K E, et al. PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40phox[J]. Nat CellBiol, 2001;3:679–682.
[42] Kuribayashi F, Nunoi H, Wakamatsu K, et al.The adaptor protein p40phox as a positive regulator of the super- oxide-producing phagocyte oxidase[J]. EMBO, 2002; 21: 6312-6320.
[43] Lopes LR, Dagher MC, Gutierrez A, et al. Phosphorylated p40phox as a negative regulator of NADPH oxidase[J]. Biochemistry, 2004; 43:3723- 3730.
[44] Duranteau J, Chandel NS, Kulisz A, et al.Intracellular signaling by reactive oxygen species during hypoxia in cardiomyocytes[J]. Biol Chem, 1998; 273: 11619-11624.
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