Yoshikawa Yoshiro, Hagihara Hiroji, Ohga Yoshimi, Nakajima-Takenaka Chikako, Murata Ken-ya, Taniguchi Shigeki, Takaki Miyako
Dept. of Physiology II, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan.
Am J Physiol Heart Circ Physiol. 2005 Apr;288(4):H1690-8. doi: 10.1152/ajpheart.00666.2004. Epub 2004 Nov 4.
We hypothesized that calpain inhibitor-1 protected left ventricular (LV) function from ischemia-reperfusion injury by inhibiting the proteolysis of alpha-fodrin. To test this hypothesis, we investigated the effect of calpain inhibitor-1 on LV mechanical work and energetics in the cross-circulated rat hearts that underwent 15-min global ischemia and 60-min reperfusion (n = 9). After ischemia-reperfusion with calpain inhibitor-1, mean end-systolic pressure at midrange LV volume and systolic pressure-volume area (PVA) at midrange LV volume (total mechanical energy per beat) were hardly changed, although they were significantly (P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. Mean myocardial oxygen consumption per beat (Vo(2)) intercepts (PVA-independent Vo(2); Vo(2) for the total Ca(2+) handling in excitation-contraction coupling and basal metabolism) of Vo(2)-PVA linear relations were also unchanged after ischemia-reperfusion with calpain inhibitor-1, although they were significantly (P < 0.01) decreased after ischemia-reperfusion without calpain inhibitor-1. There were no significant differences in O(2) costs of LV PVA and contractility among the hearts in control (or normal) postischemia-reperfusion and postischemia-reperfusion with calpain inhibitor-1. Western blot analysis of alpha-fodrin and the immunostaining of 150-kDa products of alpha-fodrin confirmed that calpain inhibitor-1 almost completely protected the proteolysis of alpha-fodrin. Our results indicate that calpain inhibitor-1 prevents the heart from ischemia-reperfusion injury associated with the impairment of total Ca(2+) handling by directly inhibiting the proteolysis of alpha-fodrin.
我们推测，钙蛋白酶抑制剂-1通过抑制α-血影蛋白的蛋白水解来保护左心室（LV）功能免受缺血再灌注损伤。为了验证这一假设，我们研究了钙蛋白酶抑制剂-1对经历15分钟全心缺血和60分钟再灌注的交叉循环大鼠心脏左心室机械功和能量代谢的影响（n = 9）。在使用钙蛋白酶抑制剂-1进行缺血再灌注后，左心室中等容量时的平均收缩末期压力和左心室中等容量时的收缩压-容积面积（PVA，每搏总机械能）几乎没有变化，尽管在未使用钙蛋白酶抑制剂-1进行缺血再灌注后它们显著降低（P < 0.01）。每搏平均心肌耗氧量（Vo₂）截距（与PVA无关的Vo₂；兴奋-收缩偶联中总Ca²⁺处理和基础代谢的Vo₂）在使用钙蛋白酶抑制剂-1进行缺血再灌注后也没有变化，尽管在未使用钙蛋白酶抑制剂-1进行缺血再灌注后它们显著降低（P < 0.01）。在对照（或正常）缺血再灌注心脏和使用钙蛋白酶抑制剂-1的缺血再灌注心脏中，左心室PVA和收缩性的O₂消耗没有显著差异。α-血影蛋白的蛋白质印迹分析和α-血影蛋白150-kDa产物的免疫染色证实，钙蛋白酶抑制剂-1几乎完全保护了α-血影蛋白的蛋白水解。我们的结果表明，钙蛋白酶抑制剂-1通过直接抑制α-血影蛋白的蛋白水解，防止心脏发生与总Ca²⁺处理受损相关的缺血再灌注损伤。
