Reduced inotropic reserve and increased susceptibility to cardiac ischemia/reperfusion injury in phosphocreatine-deficient guanidinoacetate-N-methyltransferase-knockout mice
Reduced inotropic reserve and increased susceptibility to cardiac ischemia/reperfusion injury in phosphocreatine-deficient guanidinoacetate-N-methyltransferase-knockout mice
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DOI：
10.1161/01.cir.0000165147.99592.01
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发表时间：
2005-05-17
期刊：
影响因子：
37.8
通讯作者：
Neubauer, S
中科院分区：
文献类型：
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作者：
ten Hove, M;Lygate, CA;Neubauer, S
背景-肌酸激酶(CK)/磷酸肌酸（PCr）能量缓冲和转运系统在心脏中的作用尚不清楚。胍苷乙酸- n -甲基转移酶敲除（-/-）)小鼠代表了一种深刻改变心脏能量的新模型，显示出不可检测的PCr和肌酸水平以及前体（磷酸-）胍苷乙酸（P-GA）的积累。为了描述严重受损的CK/PCr系统在心脏中的作用，我们研究了野生型（WT）和GAMT（-/-）小鼠的心脏表型。方法与结果- GAMT（-/-）小鼠未表现出心肌肥厚（心肌细胞横截面积、肥厚标志物心房利钠因子和β-肌球蛋白重链）。有创（左心室导电管）和无创（MRI）测量的收缩和舒张功能在WT和GAMT（-/-）小鼠中相似。然而，在用多巴酚丁胺进行肌力刺激时，在GAMT（-/-）心脏中，预负荷可恢复的中风工作未能达到最大表现水平(WT组为101 +/- 8mmhg，而GAMT（-/-）组为59 +/- 7mmhg；P < 0.05)。P-31-MR光谱实验表明，在肌力刺激期间，分离的WT心脏使用PCr，而分离的GAMT（-/-）心脏使用P-GA。缺血/再灌注时，GAMT（-/-）心脏在再灌注时表现出明显的收缩恢复（24%比53%的压积恢复率，P < 0.05）和舒张功能(例如，左室舒张末期压在wt和GAMT（-/-）分别为23 +/- 9和51 +/- 5 mmHg；P < 0.05)和P- ga不完全再合成。结论- GAMT（-/-）小鼠在低负荷下不发生肥厚，心功能正常，提示在静息条件下不需要功能完善的CK/PCr系统。然而，当肌力刺激或缺血/再灌注引起急性应激时，GAMT（-/-）小鼠表现出明显异常的表型，这表明在心脏工作增加或急性应激的情况下，需要一个完整的、高容量的CK/PCr系统。
Background - The role of the creatine kinase (CK)/phosphocreatine (PCr) energy buffer and transport system in heart remains unclear. Guanidinoacetate-N-methyltransferase-knockout (GAMT(-/-)) mice represent a new model of profoundly altered cardiac energetics, showing undetectable levels of PCr and creatine and accumulation of the precursor (phospho-) guanidinoacetate (P-GA). To characterize the role of a substantially impaired CK/PCr system in heart, we studied the cardiac phenotype of wild-type (WT) and GAMT(-/-) mice.Methods and Results - GAMT(-/-) mice did not show cardiac hypertrophy ( myocyte cross-sectional areas, hypertrophy markers atrial natriuretic factor and β-myosin heavy chain). Systolic and diastolic function, measured invasively ( left ventricular conductance catheter) and noninvasively (MRI), were similar for WT and GAMT(-/-) mice. However, during inotropic stimulation with dobutamine, preload-recruitable stroke work failed to reach maximal levels of performance in GAMT(-/-) hearts ( 101 +/- 8 mm Hg in WT versus 59 +/- 7 mmHg in GAMT(-/-); P < 0.05). P-31-MR spectroscopy experiments showed that during inotropic stimulation, isolated WT hearts utilized PCr, whereas isolated GAMT(-/-) hearts utilized P-GA. During ischemia/reperfusion, GAMT(-/-) hearts showed markedly impaired recovery of systolic (24% versus 53% rate pressure product recovery; P < 0.05) and diastolic function (eg, left ventricular end-diastolic pressure 23 +/- 9 inWT and 51 +/- 5 mmHg in GAMT(-/-) during reperfusion; P < 0.05) and incomplete resynthesis of P-GA.Conclusions - GAMT(-/-) mice do not develop hypertrophy and show normal cardiac function at low workload, suggesting that a fully functional CK/PCr system is not essential under resting conditions. However, when acutely stressed by inotropic stimulation or ischemia/reperfusion, GAMT(-/-) mice exhibit a markedly abnormal phenotype, demonstrating that an intact, high-capacity CK/PCr system is required for situations of increased cardiac work or acute stress.