Specific enhancement of sarcomeric response to Ca2+ protects murine myocardium against ischemia-reperfusion dysfunction
Specific enhancement of sarcomeric response to Ca2+ protects murine myocardium against ischemia-reperfusion dysfunction
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DOI：
10.1152/ajpheart.00520.2005
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发表时间：
2005-11-01
影响因子：
4.8
通讯作者：
Solaro, RJ
中科院分区：
文献类型：
--
作者：
Arteaga, GM;Warren, CM;Solaro, RJ
肌丝对Ca ~（2+）反应的改变是缺血再灌注（I/R）后心功能下降的主要机制。我们检验了心肌对Ca 2+反应增加的心脏对I/R不太敏感的假设。在一种方法中，我们研究了转基因（TG）小鼠与肌丝Ca 2+敏感性的组成性增加，其中成人形式的心肌肌钙蛋白I（cTnI）是化学计量取代胚胎/新生儿亚型，慢骨骼肌钙蛋白I（ssTnI）。我们还用EMD-57033研究了小鼠心脏，EMD-57033特异性地增强肌丝对Ca 2+的反应。我们进行了隔离，灌注心脏的I/R协议，包括25分钟的无血流缺血，然后再灌注30分钟。I/R后，非转基因（NTG）对照组心脏的压力和压力变化率显著降低，舒张末期压显著升高。这些变化在再灌注期间用EMD-57033灌注的TG心脏和NTG心脏中显著减弱，功能恢复到接近基线水平。钙离子和跨桥依赖的激活，蛋白质分解，磷酸化洗涤剂提取的纤维束进行了研究。I/R后，NTG纤维束表现出显着的抑制跨桥依赖性激活和Ca 2+激活的张力和长度依赖性的激活，是不明显的TG制剂。只有NTG心脏显示cTnI磷酸化显著增加。我们的研究结果支持这一假设，即肌丝Ca 2+敏感性的特异性增加能够减少I/R对心脏功能的影响。
Alteration in myofilament response to Ca2+ is a major mechanism for depressed cardiac function after ischemia-reperfusion (I/R) dysfunction. We tested the hypothesis that hearts with increased myofilament response to Ca2+ are less susceptible to I/R. In one approach, we studied transgenic (TG) mice with a constitutive increase in myofilament Ca2+ sensitivity in which the adult form of cardiac troponin I (cTnI) is stoichiometrically replaced with the embryonic/neonatal isoform, slow skeletal TnI (ssTnI). We also studied mouse hearts with EMD-57033, which acts specifically to enhance myofilament response to Ca2+. We subjected isolated, perfused hearts to an I/R protocol consisting of 25 min of no-flow ischemia followed by 30 min of reperfusion. After I/R, developed pressure and rates of pressure change were significantly depressed and end-diastolic pressure was significantly elevated in nontransgenic (NTG) control hearts. These changes were significantly blunted in TG hearts and in NTG hearts perfused with EMD-57033 during reperfusion, with function returning to nearly baseline levels. Ca2+- and cross bridge-dependent activation, protein breakdown, and phosphorylation in detergent-extracted fiber bundles were also investigated. After I/R NTG fiber bundles exhibited a significant depression of cross bridge-dependent activation and Ca2+-activated tension and length dependence of activation that were not evident in TG preparations. Only NTG hearts demonstrated a significant increase in cTnI phosphorylation. Our results support the hypothesis that specific increases in myofilament Ca2+ sensitivity are able to diminish the effect of I/R on cardiac function.