Therapeutic Potential of a Novel Necrosis Inhibitor for Mitochondria in Myocardial Ischemia-Reperfusion Injury Han-Mo Yang1, Ju-Young Kim1, In-Chang Hwang1, Joonoh Kim1, Joo-Eun Lee1, Mika Jeon1, Sahmin Lee2, Hyo-Soo Kim1 1Department of Internal Medicine, Seoul National University Hospital, 2Department of Internal Medicine, Asan Medical Center, Seoul, South Korea
Opening of mitochondrial permeability transition pore (mPTP) and Ca2+ overload are main contributors to myocardial ischemia-reperfusion (I/R) injury, which paradoxically causes a wide variety of myocardial damage. We investigated the protective role of a novel necrosis inhibitor (NecroX-7; NecX) against myocardial I/R injury, using in vitro and in vivo models.H9C2 rat cardiomyoblasts and neonatal cardiomyocytes were exposed to hypoxia-reoxygenation stress, after pretreatment with NecX, vitamin C, a combination of vitamin C and E, N-acetylcysteine, an apoptosis inhibitor (Z-VAD-fmk), or cyclosporine A (CsA). The main mechanism of cell death after hypoxia-reoxygenation stress was not apoptosis but necrosis, which was prevented by NecX. Protective effect of NecX was based on its potent reactive oxygen species (ROS) scavenging activity, especially on mitochondrial ROS. NecX preserved mitochondrial membrane potential through prevention of Ca2+ influx and inhibition of mPTP opening, which was more potent than that by CsA. Using Sprague-Dawley rats exposed to myocardial ischemia for 45 minutes followed by reperfusion, we compared therapeutic efficacies of NecX with CsA, vitamin C, a combination of vitamin C and E, and 5% dextrose, each administered 5 minutes before reperfusion. NecX markedly inhibited myocardial necrosis and reduced fibrotic area, to a greater extent than did CsA and other treated groups. Additionally, NecX preserved systolic function and prevented pathologic dilatory remodeling of left ventricle.The novel necrosis inhibitor has a significant protective effect against myocardial I/R injury through inhibition of mPTP opening, indicating that it is a promising candidate for cardioprotective adjunctive measure on top of reperfusion therapy.
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