Hansson Magnus J, Llwyd Osian, Morin Didier, de Paulis Damien, Arnoux Thomas, Gouarné Caroline, Koul Sasha, Engblom Henrik, Bordet Thierry, Tissier Renaud, Arheden Haakan, Erlinge David, Halestrap Andrew P, Berdeaux Alain, Pruss Rebecca M, Schaller Sophie
Lund University, Mitochondrial Medicine and Department of Clinical Physiology and Nuclear Medicine, Clinical Sciences, 221 84 Lund, Sweden.
University of Bristol, School of Biochemistry and Bristol Cardio Vascular, Medical Sciences Building, University Walk, Bristol BS8 1TD, United Kingdom.
Eur J Pharmacol. 2015 Aug 5;760:7-19. doi: 10.1016/j.ejphar.2015.04.009. Epub 2015 Apr 17.
The mode of protection against cardiac reperfusion injury by mild hypothermia and TRO40303 was investigated in various experimental models and compared to MitoQ in vitro. In isolated cardiomyocytes subjected to hypoxia/reoxygenation, TRO40303, MitoQ and mild hypothermia delayed mPTP opening, inhibited generation of mitochondrial superoxide anions at reoxygenation and improved cell survival. Mild hypothermia, but not MitoQ and TRO40303, provided protection in a metabolic starvation model in H9c2 cells and preserved respiratory function in isolated rat heart mitochondria submitted to anoxia/reoxygenation. In the Langendorff-perfused rat heart, only mild hypothermia provided protection of hemodynamic function and reduced infarct size following ischemia/reperfusion. In biopsies from the left ventricle of pigs subjected to in vivo occlusion/reperfusion, TRO40303 specifically preserved respiratory functions in the peri-infarct zone whereas mild hypothermia preserved both the ischemic core area and the peri-infarct zones. Additionally in this pig model, only hypothermia reduced infarct size. We conclude that mild hypothermia provided protection in all models by reducing the detrimental effects of ischemia, and when initiated before occlusion, reduced subsequent reperfusion damage leading to a smaller infarct. By contrast, although TRO40303 provided similar protection to MitoQ in vitro and offered specific protection against some aspects of reperfusion injury in vivo, this was insufficient to reduce infarct size.
在各种实验模型中研究了轻度低温和TRO40303对心脏再灌注损伤的保护模式，并在体外与MitoQ进行了比较。在经历缺氧/复氧的分离心肌细胞中，TRO40303、MitoQ和轻度低温延迟了线粒体通透性转换孔（mPTP）的开放，抑制了复氧时线粒体超氧阴离子的产生，并改善了细胞存活。轻度低温在H9c2细胞的代谢饥饿模型中提供了保护，但MitoQ和TRO40303没有，并且在经历缺氧/复氧的分离大鼠心脏线粒体中保留了呼吸功能。在Langendorff灌注的大鼠心脏中，只有轻度低温在缺血/再灌注后提供了血流动力学功能保护并减小了梗死面积。在体内经历闭塞/再灌注的猪左心室活检中，TRO40303特异性地保留了梗死周边区域的呼吸功能，而轻度低温则同时保留了缺血核心区域和梗死周边区域。此外，在该猪模型中，只有低温减小了梗死面积。我们得出结论，轻度低温通过减少缺血的有害影响在所有模型中提供了保护，并且在闭塞前开始时，减少了随后的再灌注损伤，导致梗死面积减小。相比之下，尽管TRO40303在体外提供了与MitoQ类似的保护，并在体内对再灌注损伤的某些方面提供了特异性保护，但这不足以减小梗死面积。
