Interplay between Ca2+ cycling and mitochondrial permeability transition pores promotes reperfusion-induced injury of cardiac myocytes.
Interplay between Ca2+ cycling and mitochondrial permeability transition pores promotes reperfusion-induced injury of cardiac myocytes.
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DOI：
10.1111/j.1582-4934.2010.01249.x
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发表时间：
2011-11
影响因子：
5.3
通讯作者：
Ladilov Y
中科院分区：
文献类型：
--
作者：
Abdallah Y;Kasseckert SA;Iraqi W;Said M;Shahzad T;Erdogan A;Neuhof C;Gündüz D;Schlüter KD;Tillmanns H;Piper HM;Reusch HP;Ladilov Y
肌浆网（SR）中Ca 2+的不受控制的释放有助于再灌注诱导的心肌细胞损伤，例如过度收缩和坏死。为了找出这种现象的潜在细胞机制，我们研究了线粒体通透性转换孔（MPTP）的开放，导致ATP耗竭和活性氧（ROS）的形成，是否可能参与。为此目的，成年大鼠心肌细胞进行模拟缺血和再灌注。MPTP开放通过钙黄绿素释放和通过监测Δ Δ λ m来检测。在用MnCl 2淬灭胞质隔室后，Fura-2用于监测胞质[Ca 2 +]i或线粒体钙[Ca 2 +]m。用MitoSOX Red检测线粒体ROS [ROS]m的产生，并使用mag-fura-2监测Mg 2+浓度，其反映细胞ATP的变化。通过碘化丙啶染色确定坏死。再灌注导致线粒体钙黄绿素释放，Δ Δ CaM塌陷和ATP恢复障碍。同时，细胞内出现钙振荡，[Ca ~（2+）]m和[ROS]m升高，细胞过度收缩，坏死。用thapsigargine或ryanodine抑制SR驱动的Ca 2+循环防止线粒体功能障碍、ROS形成和MPTP开放。抑制线粒体Ca ~（2+）摄取（Ru 360）或MPTP（环孢霉素A）显著减弱Ca ~（2+）循环、过度挛缩和坏死。ROS清除剂（2-巯基丙酰甘氨酸或N-乙酰半胱氨酸）对这些参数没有影响，但降低[ROS]m。总之，MPTP开放发生在再灌注早期，是由于Ca 2+振荡主要来自SR和MPTP的支持。Ca ~（2+）循环和MPTP的相互作用促进了再灌注诱导的心肌细胞过度收缩和坏死。线粒体ROS的形成是MPTP开放的结果而不是原因。
Uncontrolled release of Ca2+ from the sarcoplasmic reticulum (SR) contributes to the reperfusion-induced cardiomyocyte injury, e.g. hypercontracture and necrosis. To find out the underlying cellular mechanisms of this phenomenon, we investigated whether the opening of mitochondrial permeability transition pores (MPTP), resulting in ATP depletion and reactive oxygen species (ROS) formation, may be involved. For this purpose, isolated cardiac myocytes from adult rats were subjected to simulated ischemia and reperfusion. MPTP opening was detected by calcein release and by monitoring the ΔΨm. Fura-2 was used to monitor cytosolic [Ca2+]i or mitochondrial calcium [Ca2+]m, after quenching the cytosolic compartment with MnCl2. Mitochondrial ROS [ROS]m production was detected with MitoSOX Red and mag-fura-2 was used to monitor Mg2+ concentration, which reflects changes in cellular ATP. Necrosis was determined by propidium iodide staining. Reperfusion led to a calcein release from mitochondria, ΔΨm collapse and disturbance of ATP recovery. Simultaneously, Ca2+ oscillations occurred, [Ca2+]m and [ROS]m increased, cells developed hypercontracture and underwent necrosis. Inhibition of the SR-driven Ca2+ cycling with thapsigargine or ryanodine prevented mitochondrial dysfunction, ROS formation and MPTP opening. Suppression of the mitochondrial Ca2+ uptake (Ru360) or MPTP (cyclosporine A) significantly attenuated Ca2+ cycling, hypercontracture and necrosis. ROS scavengers (2-mercaptopropionyl glycine or N-acetylcysteine) had no effect on these parameters, but reduced [ROS]m. In conclusion, MPTP opening occurs early during reperfusion and is due to the Ca2+ oscillations originating primarily from the SR and supported by MPTP. The interplay between Ca2+ cycling and MPTP promotes the reperfusion-induced cardiomyocyte hypercontracture and necrosis. Mitochondrial ROS formation is a result rather than a cause of MPTP opening.
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影响因子：
64.8
作者：
Nakagawa, T;Shimizu, S;Tsujimoto, Y
通讯作者：
Tsujimoto, Y
DOI：
10.1152/ajpheart.01183.2004
发表时间：
2005-06-01
影响因子：
4.8
作者：
Sumida, T;Otani, H;Imamura, H
通讯作者：
Imamura, H
DOI：
10.1083/jcb.142.4.975
发表时间：
1998-08-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Duchen MR;Leyssens A;Crompton M
通讯作者：
Crompton M
影响因子：
20.1
作者：
Maack, Christoph;Cortassa, Sonia;O'Rourke, Brian
通讯作者：
O'Rourke, Brian
影响因子：
37.8
作者：
MIYAZAKI, S;FUJIWARA, H;HAMASHIMA, Y
通讯作者：
HAMASHIMA, Y