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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.

我们建立了Ryanodine受体2型(RyR-2(+/-))基因敲除小鼠，并对心脏功能进行了研究。在Langenforff灌流中，我们没有检测到K.O小鼠心脏的压力参数(dp/dt，-dp/dt)和舒张末容量有任何明显的变化。我们的结论是，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钙泵(SERCA2a)在[Ca^&lt；2+&gt；]i调节中的重要作用，并对其心脏功能进行了研究。TG组的-P/dt和-dp/dt均大于非TG组(NTG)。在TG组，当心脏负荷较高时，心肌肥厚明显减轻。因此，SERCA2a在改善病理生理适应中起着关键作用。我们解剖左心室乳头肌，用去甲肾上腺素测定钙瞬变(CAT)。CAT的峰值大于NTG。TG组CAT的时间进程快于NTG组。在NTG中，异丙肾上腺素增加了CAT的峰值，缩短了CAT的时间。然而，在TO中，这些参数没有明显的变化。在CO_2酸中毒时，收缩减少，而在NTG时，CAT升高。在TO中，也观察到了类似的变化，但对酸中毒收缩的抑制作用减弱。收缩功能恢复情况也好于NTG组。因此，SERCA2a在病理生理条件下起着关键作用。