CGP37157对心肌细胞钙循环影响的机理研究
摘要
目的:
目前线粒体钠钙交换体特异性阻断剂CGP37157对心肌细胞肌浆网钙释放、钙回摄的影响缺乏研究。因此,本实验旨在探讨CGP37157对心肌细胞钙循环的影响。
方法:
(1)心室肌组织ATP含量的测定:32只雄性SD大鼠随机分组,每组8只。以含60μmol/L Ca~(2+)台氏液(对照组)和含有CGP37157的台氏液(实验组)灌流心肌组织,分别灌流15min、30min、60min。灌流结束后,用剪刀剪取左心室少许心肌组织,采用ATP检测试剂盒(ATP Assay Kit)测定其中ATP的含量;
(2)心肌细胞形态学观察:分组及心肌组织的灌流方法同(1),灌流结束后,用剪刀剪取左心室少许心肌组织,用于透射电子显微镜的制样及观察;
(3)心肌组织cAMP含量的测定:分组及心肌组织灌流方法同(1),灌流结束后,用剪刀剪取左心室少许心肌组织,应用双抗体夹心酶标免疫分析法测定标本中大鼠环磷酸腺苷(cAMP)水平;
(4)静息期心肌细胞钙循环的测定:SD大鼠,每组10只,共两组。采用常规酶解法分离心肌细胞,Fluo-3/AM负载心肌细胞,用激光扫描共聚焦显微镜观察;
(5)收缩期心肌细胞钙瞬变的测定:SD大鼠,每组10只,共两组。采用常规酶解法分离心肌细胞,Fluo-3/AM负载心肌细胞,用全细胞膜片钳-激光扫描共聚焦显微镜联机技术同步记录系统记录各组大鼠心肌细胞L-型钙电流(ICa,L)和胞浆内钙瞬变(即钙诱导钙瞬变),对照组不灌流CGP37157,实验组灌流CGP37157(10μmol/L);
(6)统计学分析:利用SPSS11.5统计软件进行数据处理,所有数据以均数±标准差( (X|—)±SD)表示,两组间均数的比较采用t检验,率的比较采用x~2检验。P<0.05为差异有统计学意义。
结果:
(1)透射电子显微镜形态学观察:CGP37157引起心肌细胞线粒体结构异常,表现为不同程度的线粒体嵴溶解,并且作用时间越长,线粒体受损伤越重;
(2)心室肌组织中ATP含量的比较:对照组、15min、30min、60min各组测得的ATP的浓度依次是1.23±0.02μM/L、0.75±0.01μM/L、0.44±0.02μM/L、0.17±0.01μM/L,各实验组较对照组ATP含量显著减少(n=10, P<0.05);60min组较30minATP含量显著减少(0.17±0.01μM/L VS 0.44±0.02μM/L, n=8, P<0.01);
(3)心肌组织中cAMP含量的比较:CGP37157引起心肌组织cAMP的含量增加,对照组15min、30min、60min各组测得的cAMP的含量分别为791±35pMol/g、1101±55pMol/g、1525±40pMol/g、2017±60pMol/g;60min组较对照组cAMP含量显著增加(n=8,P<0.05);(4)对静息期肌浆网钙循环的影响:钙释放速率实验组(5.02±0.015)比对照组显著增强(1.01±0.006,n=10,P<0.01);钙存储实验组(20.2±0.8)比对照组显著减小(0.3±0.3, n=10, P<0.01);钙回摄速率实验组(1.08±0.15)与对照组没有差异(0.99±0.09,n=10,P>0.05);(5)收缩期心肌细胞的钙瞬变:ICa,L的电流密度实验组(2.02±0.16pA/pF)比对照组显著减少(0.69±0.07pA/pF, n=10, P<0.01);实验组(45.5±5.2)大鼠CICR过程中钙释放的幅度显著低于对照组(23.2±4.8,n=10,P<0.01)。
结论:
CGP37157导致心肌细胞钙循环的异常,原因可能为其导致线粒体受损和PKA通路异常。具体如下:
(1)CGP37157导致线粒体的损伤,表现为其结构受损和ATP合成下降。
(2)CGP37157介导的线粒体损伤导致静息期心肌细胞钙循环异常,表现为促进肌浆网钙泄漏,但不影响其钙回摄。
(3)CGP37157导致cAMP增加,导致PKA激活增强,可能导致静息期肌浆网钙泄漏。
(4)CGP37157导致收缩期心肌细胞I_(Ca,L)电流密度减小,进而导致其钙瞬变幅度减小。
Object:
Because of less research on the cardiac sarcoplasmic reticulum calcium cycle produced by CGP37157, as specific mitochondrial Sodium-Calcium exchanger (mNCX), it is employed to investigate its influence on ventricular myocyte calcium cycling.
Methods:
(1)The measurement of cardiac ATP content: 32 SD rats were randomly divided into four groups. After perfusing heart with 60μmol/L calcium Tyrode's solution(control group) and CGP37157-Tyrode's solution(experiment group), a few cardiac tissue is chosen to measure the ATP content in different groups with ATP Assay Kit.(2)Morphological observation: the former steps like rats groups and perfusion follows (1), then a ventricular tissue is taken away and used as transmission electron microscope(TEM) experiments.(3)The measurement of cAMP content: the former steps like rats groups and perfusion follows (1), a few ventricular tissue is used to measure cAMP content in different groups with enzyme linked immunoassay(ELISA) cAMP Kit.(4)Recording diastolic calcium cycling in ventricular myocytes: 20 SD rats were equally and randomly divided into two groups, and isolated ventricular myocytes with collagenase. After incubating myocytes with Fluo-3/AM, Laser scanning confocal microscope(LSCM) is employed to record the calcium transient. (5)Recording calcium transient in systolic ventricular myocytes: the former steps like rats groups and isolation follows (4), after incubation with Fluo-3/AM, whole cell patch-LSCM system chronically records L-type calcium current(ICa,L) and cytosolic calcium transient. (6)statistic analysis: SPSS11.5 is employed and all the data are presented as mean±SEM, and t-test and x~2 test was used for the statistical analysis. P-values of <0.05 were considered significant.
Results:
(1)Morphological observation with TEM: CGP37157 caused structural changes in ventricular myocytes, leading to the lysis of mitochondrial cristae and the injury was more serious after longer perfusion. (2)ATP content in ventricular tissue: after perfusion with CGP37157, ATP content significantly decreased(0.75±0.01μM/L、0.44±0.02μM/L、0.17±0.01μM/L VS 1.23±0.02μM/L, n=8, P<0.05); 60min group greatly decreased than 30min (0.17±0.01μM/L VS 0.44±0.02μM/L, n=8, P<0.01); (3)cAMP content in ventricular tissue:CGP37157 leads cAMP content increased, the content as follows: 791±35pMol/g、1101±55pMol/g、1525±40pMol/g、2017±60pMol/g; 60 min group cAMP increased significantly(n=8, P<0.05); (4)Diastolic calcium cycling in ventricular myocytes:calcium efflux was significantly increased in experiment group and control group(5.02±0.015 VS 1.01±0.006, n=10, P<0.01); calcium influx was not changed(1.08±0.15VS 0.99±0.09,n=10,P>0.05); calcium storage was decreased(20.2±0.8 VS 0.3±0.3, n=10, P<0.01 ); (5)Systolic calcium cycling in ventricular myocytes: ICa,L was significantly decreased in experiment group than in control group(2.02±0.16pA/pF VS 0.69±0.07pA/pF, n=10, P<0.01); the amplitude of calcium transient was significantly decreased (45.5±5.2 VS 23.2±4.8,n=10,P<0.01 );
Conclusions:
CGP37157 caused abnormal ventricular calcium cycling, which may due to mitochondrial injury and is associated with abnormal PKA signal pathway.
(1) CGP37157 caused mitochondrial injury, with damaged structure and decreased ATP production;
(2) CGP37157-mediated mitochondrial injury caused abnormal diastolic calcium cycling, along with increased calcium efflux;
(3) CGP37157 leads increased cAMP in ventricular myocytes, and then activated PKA activity, it might lead to systolic calcium leak;
(4) CGP37157 caused decreased current density of ICa,L, and thus leaded to lower calcium transient amplitude.
目前线粒体钠钙交换体特异性阻断剂CGP37157对心肌细胞肌浆网钙释放、钙回摄的影响缺乏研究。因此,本实验旨在探讨CGP37157对心肌细胞钙循环的影响。
方法:
(1)心室肌组织ATP含量的测定:32只雄性SD大鼠随机分组,每组8只。以含60μmol/L Ca~(2+)台氏液(对照组)和含有CGP37157的台氏液(实验组)灌流心肌组织,分别灌流15min、30min、60min。灌流结束后,用剪刀剪取左心室少许心肌组织,采用ATP检测试剂盒(ATP Assay Kit)测定其中ATP的含量;
(2)心肌细胞形态学观察:分组及心肌组织的灌流方法同(1),灌流结束后,用剪刀剪取左心室少许心肌组织,用于透射电子显微镜的制样及观察;
(3)心肌组织cAMP含量的测定:分组及心肌组织灌流方法同(1),灌流结束后,用剪刀剪取左心室少许心肌组织,应用双抗体夹心酶标免疫分析法测定标本中大鼠环磷酸腺苷(cAMP)水平;
(4)静息期心肌细胞钙循环的测定:SD大鼠,每组10只,共两组。采用常规酶解法分离心肌细胞,Fluo-3/AM负载心肌细胞,用激光扫描共聚焦显微镜观察;
(5)收缩期心肌细胞钙瞬变的测定:SD大鼠,每组10只,共两组。采用常规酶解法分离心肌细胞,Fluo-3/AM负载心肌细胞,用全细胞膜片钳-激光扫描共聚焦显微镜联机技术同步记录系统记录各组大鼠心肌细胞L-型钙电流(ICa,L)和胞浆内钙瞬变(即钙诱导钙瞬变),对照组不灌流CGP37157,实验组灌流CGP37157(10μmol/L);
(6)统计学分析:利用SPSS11.5统计软件进行数据处理,所有数据以均数±标准差( (X|—)±SD)表示,两组间均数的比较采用t检验,率的比较采用x~2检验。P<0.05为差异有统计学意义。
结果:
(1)透射电子显微镜形态学观察:CGP37157引起心肌细胞线粒体结构异常,表现为不同程度的线粒体嵴溶解,并且作用时间越长,线粒体受损伤越重;
(2)心室肌组织中ATP含量的比较:对照组、15min、30min、60min各组测得的ATP的浓度依次是1.23±0.02μM/L、0.75±0.01μM/L、0.44±0.02μM/L、0.17±0.01μM/L,各实验组较对照组ATP含量显著减少(n=10, P<0.05);60min组较30minATP含量显著减少(0.17±0.01μM/L VS 0.44±0.02μM/L, n=8, P<0.01);
(3)心肌组织中cAMP含量的比较:CGP37157引起心肌组织cAMP的含量增加,对照组15min、30min、60min各组测得的cAMP的含量分别为791±35pMol/g、1101±55pMol/g、1525±40pMol/g、2017±60pMol/g;60min组较对照组cAMP含量显著增加(n=8,P<0.05);(4)对静息期肌浆网钙循环的影响:钙释放速率实验组(5.02±0.015)比对照组显著增强(1.01±0.006,n=10,P<0.01);钙存储实验组(20.2±0.8)比对照组显著减小(0.3±0.3, n=10, P<0.01);钙回摄速率实验组(1.08±0.15)与对照组没有差异(0.99±0.09,n=10,P>0.05);(5)收缩期心肌细胞的钙瞬变:ICa,L的电流密度实验组(2.02±0.16pA/pF)比对照组显著减少(0.69±0.07pA/pF, n=10, P<0.01);实验组(45.5±5.2)大鼠CICR过程中钙释放的幅度显著低于对照组(23.2±4.8,n=10,P<0.01)。
结论:
CGP37157导致心肌细胞钙循环的异常,原因可能为其导致线粒体受损和PKA通路异常。具体如下:
(1)CGP37157导致线粒体的损伤,表现为其结构受损和ATP合成下降。
(2)CGP37157介导的线粒体损伤导致静息期心肌细胞钙循环异常,表现为促进肌浆网钙泄漏,但不影响其钙回摄。
(3)CGP37157导致cAMP增加,导致PKA激活增强,可能导致静息期肌浆网钙泄漏。
(4)CGP37157导致收缩期心肌细胞I_(Ca,L)电流密度减小,进而导致其钙瞬变幅度减小。
Object:
Because of less research on the cardiac sarcoplasmic reticulum calcium cycle produced by CGP37157, as specific mitochondrial Sodium-Calcium exchanger (mNCX), it is employed to investigate its influence on ventricular myocyte calcium cycling.
Methods:
(1)The measurement of cardiac ATP content: 32 SD rats were randomly divided into four groups. After perfusing heart with 60μmol/L calcium Tyrode's solution(control group) and CGP37157-Tyrode's solution(experiment group), a few cardiac tissue is chosen to measure the ATP content in different groups with ATP Assay Kit.(2)Morphological observation: the former steps like rats groups and perfusion follows (1), then a ventricular tissue is taken away and used as transmission electron microscope(TEM) experiments.(3)The measurement of cAMP content: the former steps like rats groups and perfusion follows (1), a few ventricular tissue is used to measure cAMP content in different groups with enzyme linked immunoassay(ELISA) cAMP Kit.(4)Recording diastolic calcium cycling in ventricular myocytes: 20 SD rats were equally and randomly divided into two groups, and isolated ventricular myocytes with collagenase. After incubating myocytes with Fluo-3/AM, Laser scanning confocal microscope(LSCM) is employed to record the calcium transient. (5)Recording calcium transient in systolic ventricular myocytes: the former steps like rats groups and isolation follows (4), after incubation with Fluo-3/AM, whole cell patch-LSCM system chronically records L-type calcium current(ICa,L) and cytosolic calcium transient. (6)statistic analysis: SPSS11.5 is employed and all the data are presented as mean±SEM, and t-test and x~2 test was used for the statistical analysis. P-values of <0.05 were considered significant.
Results:
(1)Morphological observation with TEM: CGP37157 caused structural changes in ventricular myocytes, leading to the lysis of mitochondrial cristae and the injury was more serious after longer perfusion. (2)ATP content in ventricular tissue: after perfusion with CGP37157, ATP content significantly decreased(0.75±0.01μM/L、0.44±0.02μM/L、0.17±0.01μM/L VS 1.23±0.02μM/L, n=8, P<0.05); 60min group greatly decreased than 30min (0.17±0.01μM/L VS 0.44±0.02μM/L, n=8, P<0.01); (3)cAMP content in ventricular tissue:CGP37157 leads cAMP content increased, the content as follows: 791±35pMol/g、1101±55pMol/g、1525±40pMol/g、2017±60pMol/g; 60 min group cAMP increased significantly(n=8, P<0.05); (4)Diastolic calcium cycling in ventricular myocytes:calcium efflux was significantly increased in experiment group and control group(5.02±0.015 VS 1.01±0.006, n=10, P<0.01); calcium influx was not changed(1.08±0.15VS 0.99±0.09,n=10,P>0.05); calcium storage was decreased(20.2±0.8 VS 0.3±0.3, n=10, P<0.01 ); (5)Systolic calcium cycling in ventricular myocytes: ICa,L was significantly decreased in experiment group than in control group(2.02±0.16pA/pF VS 0.69±0.07pA/pF, n=10, P<0.01); the amplitude of calcium transient was significantly decreased (45.5±5.2 VS 23.2±4.8,n=10,P<0.01 );
Conclusions:
CGP37157 caused abnormal ventricular calcium cycling, which may due to mitochondrial injury and is associated with abnormal PKA signal pathway.
(1) CGP37157 caused mitochondrial injury, with damaged structure and decreased ATP production;
(2) CGP37157-mediated mitochondrial injury caused abnormal diastolic calcium cycling, along with increased calcium efflux;
(3) CGP37157 leads increased cAMP in ventricular myocytes, and then activated PKA activity, it might lead to systolic calcium leak;
(4) CGP37157 caused decreased current density of ICa,L, and thus leaded to lower calcium transient amplitude.
引文
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[41]Valentina Lissandron, Manuela Zaccolo.Compartmentalized cAMP/PKA signalling regulates cardiac excitation-contraction coupling coupling.J.Journal of Muscle Research and Cell Motility,2006,27(5-7): 399-403.
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[44] Fatt P, Katz B.The electrical properties of crustacean muscle fibres.J.Physiol.1953,120:171-204.
[45] Lehnart SE,Wehrens XH,Marks AR.Calstabin deficiency,ryanodine receptors and sudden cardiac death.J.Biochem Biophys Res Commun,2004,322(4) :1267-1279.
[46] Lothar A. Blatter, Jens Kocksk?mper, Katherine A. Sheehan, Aleksey V. Zima, J?rg Hüser and Stephen L. Lipsius. Local calcium gradients during excitation–contraction coupling and alternans in atrial myocytes. J.J Physiol, 2003, 546(1): 19–31.
[47] Hatem SN, Benardeau A, Rucker-Martin C, Marty I, De Chamisso P, Villaz M , Mercardier J-J.Different compartments of sarcoplasmic reticulum participate in the excitation-contraction coupling process in human atrial myocytes.J. Circ Res,1997, 80: 345–353.
[48] Trafford AW, Diaz ME, Eisner DA. Coordinated control of cell Ca2+ loading and triggered release from the sarcoplasmic reticulum underlies the rapid inotropic response to increased L-type Ca2+ current.J.Circ Res 2001,88:195–201.
[49] Jiang MT, Lokuta AJ, Farrell EF, Wolff MR, Haworth RA, Valdivia HH. Abnormal Ca2+ release, but normal ryanodine receptors, in canine and human heart failure.J. Circ Res, 2002,91: 1015–1022.
[50] Thu le T, Ahn JR, Woo SH.Inhibition of L-type Ca2+ channel by mitochondrial Na+–Ca2+ exchange inhibitor CGP-37157 in rat atrial myocytes.J. Eur J Pharmacol. 2006 ,15;552(1-3): 15-9.
[51] Lipp P, Egger M, Niggli E. Spatial characteristics of sarcoplasmic reticulum Ca2+ release events triggered by L-type Ca2+ current and Na+ current in guinea-pig cardiac myocytes.J. JPhysiol 2002,542: 383–393.
[52] Xun Ai, Jerry W. Curran, Thomas R. Shannon, Donald M. Bers and Steven M. Pogwizd. Ca2+/Calmodulin–Dependent Protein Kinase Modulates Cardiac Ryanodine Receptor Phosphory- -lation and Sarcoplasmic Reticulum Ca2+ Leak in Heart Failure.J.Circ. Res,2005,97:1314-1322.
[53] Nakamura R, Egashira K, Machida Y, Hayashidani S, Takeya M, Utsumi H, Tsutsui H, Takeshita A. Probucol attenuates left ventricular dysfunction and remodeling in tachycardia-induced heart failure: roles of oxidative stress and inflammation. Circulation. 2002,106: 362–367.
[54] Chien KR, Ross J Jr, Hoshijima M. Calcium and heart failure: the cycle game.J.Nat Med. 2003,9: 508–509.
[1]Hobbs RE.Guidelines for the diagnosis and management of heart failure. Am J Ther. 2004,11(6): 467-72.
[2] Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho KK, Murabito JM, Vasan RS. Long-term trends in the incidence of and survival with heart failure.N Engl J Med. 2002,347(18):1397-402.
[3] Faiez Zannad, Serge Briancon, Yves Juilliere, Paul-Michel Mertes, Jean-Pierre Villemot, Fran?ois Alla, Jean-Marc Virion, and the EPICAL Investigators. Incidence, clinical and etiologic features, and outcomes of advanced chronic heart failure: the EPICAL study. J Am Coll Cardiol.1999; 33:734-742.
[4] Lloyd-Jones DM, Larson MG, Leip EP, Beiser A, D'Agostino RB, Kannel WB, Murabito JM, Vasan RS, Benjamin EJ, Levy D; Framingham Heart Study. Lifetime risk for developing congestive heart failure:the Framingham Heart Study.Circulation. 2002,106(24):3068-72.
[5] Adams KF Jr. New epidemiologic perspectives concerning mild-to-moderate heart failure. Am J Med. 2001 May 7;110 Suppl 7A:6S-13S.
[6] Eisner DA, Choi HS, Diaz ME, O’Neill SC, Trafford AW. Integrative analysis of calcium cycling in cardiac muscle.Circ Res. 2000,87: 1087–94.
[7] Bers DM. Cardiac excitation-contraction coupling.Nature. 2002;415:198–205.
[8] MacLennan DH, Kranias EG. Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol. 2003,4: 566–77.
[9] Satoh H, Blatter LA and Bers DM. Effects of [Ca2+]i, SR Ca2+ load, and rest on Ca2+ spark frequency in ventricular myocytes. Am J Physiol.199,272: H657-668.
[10] Hermann HP, Pieske B, Schwarzmuller E, Keul J, Just H and Hasenfuss G. Haemodynamic effects of intracoronary pyruvate in patients with congestive heart failure: an open study. Lancet. 1999,353: 1321-1323.
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