Mitochondrial Physiology Network 10.9: 96 (2005) - download pdf

Effects of NO and estrogens on ischaemia-induced permeability transition in heart mitochondria.

Vilma Borutaite¹, R Morkuniene², G Brown¹

¹Dept. Biochemistry, University of Cambridge, Cambridge, UK; ²Kaunas University of Medicine, Kaunas, Lithuania. - vb207@mole.bio.cam.ac.uk 

    Apoptosis is known to contribute to ischaemia-reperfusion induced cell death in the heart. However, the mechanism of induction of apoptosis during ischaemia or reperfusion is still unclear. Recently we have shown that global ischaemia by itself (without reperfusion) can induce cytochrome c release from mitochondria and subsequent apoptosis through opening of mitochondrial permeability transition pore (MPT) [1]. In this study we aimed to investigate whether protective action of nitric oxide (NO) and estradiol, two well known cardioprotective agents, can be associated with their effect on MPT during heart ischemia.

    NO depending on concentrations and other conditions can be cytotoxic or cytoprotective. For example, S-nitrosothiols can rapidly induce mitochondria-mediated apoptosis in the perfused heart [2]. In contrast, NO itself at relatively low concentrations can be cardioprotective. We found that short (3-5 min) pre-perfusion of hearts with micromolar concentrations of NO donor DETA/NO protected hearts from ischemia-induced cytochrome c release from mitochondria and subsequent respiratory inhibition and caspase activation. Similarly, perfusion of the hearts with 100 nM estradiol prevented the loss of cytochrome c from mitochondria and its accumulation in the cytosol as well as inhibition of mitochondrial respiration, caspase activation and nuclear apoptosis. In isolated mitochondria, estradiol prevented MPT related, high calcium induced loss of cytochrome. These data suggest that estrogens and NO can protect the myocardium against ischemia-induced apoptosis by inhibiting MPT.

1.  Borutaite V, Jekabsone A, Morkuniene R, Brown GC (2003) Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome c release and apoptosis induced by heart ischemia. J. Mol. Cell. Cardiol. 35: 357-366.

2.  Jekabsone A, Dapkunas Z, Brown GC, Borutaite V (2003) S-nitrosothiol-induced rapid cytochrome c release, caspase activation and mitochondrial permeability transition in perfused heart. Biochem. Pharmacol. 66:1513-1519.