Inhibition of the mitochondrial calcium uniporter by the oxo-bridged dinuclear ruthenium amine complex (Ru360) prevents from irreversible injury in postischemic rat heart
Inhibition of the mitochondrial calcium uniporter by the oxo-bridged dinuclear ruthenium amine complex (Ru360) prevents from irreversible injury in postischemic rat heart
复制标题
DOI：
10.1111/j.1742-4658.2005.04771.x
复制
发表时间：
2005-07-01
期刊：
影响因子：
5.4
通讯作者：
Zazueta, C
中科院分区：
文献类型：
--
作者：
García-Rivas, GD;Guerrero-Hernández, A;Zazueta, C
线粒体钙超载与再灌注心脏的不可逆损伤有关。因此，我们研究了氧桥双核钌胺络合物（Ru-360），这是一种选择性和有效的线粒体钙单向转运体阻滞剂，对线粒体功能障碍和从再灌注大鼠心脏分离的线粒体中的基质游离钙浓度的影响。Ru-360的灌注维持氧化磷酸化，并防止从再灌注心脏分离的线粒体中的线粒体渗透性转换孔的开放。我们发现，Ru-360灌注仅部分抑制线粒体钙单向转运体，维持线粒体基质游离钙浓度在基础水平，尽管高浓度的胞浆钙。此外，我们观察到灌注Ru-360既不抑制肌浆网中的Ca 2+循环，也不阻断ryanodine受体，这意味着ryanodine受体的抑制不能解释Ru-360在离体心脏中的保护作用。我们得出结论，缺血后心肌功能的维持与线粒体钙单向转运体的不完全抑制相关。因此，这种分子的化学抑制可能是一种用于预防再灌注期间心脏损伤的方法。
Mitochondrial calcium overload has been implicated in the irreversible damage of reperfused heart. Accordingly, we studied the effect of an oxygen-bridged dinuclear ruthenium amine complex (Ru-360), which is a selective and potent mitochondrial calcium uniporter blocker, on mitochondrial dysfunction and on the matrix free-calcium concentration in mitochondria isolated from reperfused rat hearts. The perfusion of Ru-360 maintained oxidative phosphorylation and prevented opening of the mitochondrial permeability transition pore in mitochondria isolated from reperfused hearts. We found that Ru-360 perfusion only partially inhibited the mitochondrial calcium uniporter, maintaining the mitochondrial matrix free-calcium concentration at basal levels, despite high concentrations of cytosolic calcium. Additionally, we observed that perfused Ru-360 neither inhibited Ca2+ cycling in the sarcoplasmic reticulum nor blocked ryanodine receptors, implying that the inhibition of ryanodine receptors cannot explain the protective effect of Ru-360 in isolated hearts. We conclude that the maintenance of postischemic myocardial function correlates with an incomplete inhibition of the mitochondrial calcium uniporter. Thus, the chemical inhibition by this molecule could be an approach used to prevent heart injury during reperfusion.