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Intracellular Ca^<2+> regulation in the myocardium with ryanodine receptor type 2(+/-) heterozygous mouse

兰尼定受体2型(/-)杂合小鼠心肌细胞内Ca^<2>调节

基本信息

批准号：
13670048
负责人：
KURIHARA Satoshi
金额：
$ 2.18万
依托单位：
Jikei University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

We produced knockout mouse with ryanodine receptor type 2 (RyR-2(+/-)) and explored the cardiac functions of the heart. In Langenforff perfusion, we could not detect any significant changes of the parameters of pressure (dP/dt, -dP/dt) and end diastolic volume in the heart in K.O. mouse. We concluded that the partial deletion of RyR-2 is well compensated. Then, we focused on the Ca^<2+> pump of sarcoplasmic reteiculum (SERCA2a) which plays an important role in the regulation of [Ca^<2+>]i. We overexpressed SERCA 2a (TG) and explored its cardiac functions. In TG, &P/dt and-dP/dt were larger than those in nonTG (NTG). In TG, cardiac hypertrophy was significantly reduced when the heart was loaded with higher pressure. Thus, SERCA2a plays a key role to improve pathophysiological adaptation. We dissected papillary muscles from the left ventricle of TO and measured Ca^<2+> transient(CaT) with aequorin. The peak of CaT was larger than that of NTG. The time courses of CaT in TG were faster than those in NTG. In NTG, isoprenaline increased the peak of CaT and shortened the time course of CaT. However, no significant changes of these parameters were observed in TO. In CO_2 acidosis, contraction was decreased although CaT was increased in NTG. In TO, similar changes were observed but the inhibition of contraction in acidosis was reduced. The recovery of contraction was also better than that in NTG. Thus, SERCA2a plays a pivotal role under pathophysiological condition.

我们用Ryanodine受体2（RyR-2（+/-））基因敲除小鼠，并探讨了心脏的心功能。Langenforff灌流时，K.O.大鼠心脏压力（dP/dt，-dP/dt）和舒张末期容积（dD）无明显变化。老鼠.我们得出结论，RyR-2的部分缺失得到了很好的补偿。然后，我们重点研究了肌浆网Ca^2+泵（SERCA 2a）在[Ca^2+]i调节中的重要作用。我们过量表达了SERCA 2a（TG）并研究了其心脏功能。TG组的&P/dt和-dP/dt均大于非TG组（NTG）。在TG中，当心脏负荷较高的压力时，心脏肥大显著减少。因此，SERCA 2a在改善病理生理适应中起着关键作用。我们从TO的左心室解剖乳头肌，并用水母发光蛋白测量Ca^2+瞬时（CaT）。CaT的峰值大于NTG。TG组CaT的时程明显快于NTG组。异丙肾上腺素使NTG的CaT峰值增加，时间缩短，而TO的上述参数无明显变化。在CO_2酸中毒时，NTG虽使CaT升高，但收缩功能减弱。在TO中，观察到类似的变化，但酸中毒时收缩抑制减少。收缩的恢复也好于NTG。因此，SERCA 2a在病理生理条件下起着关键作用。