Abstract 263: Therapeutic Potential of a Novel Necrosis Inhibitor in Myocardial Ischemia-reperfusion Injury
Background: Reperfusion, although essential for salvage of ischemic myocardium, paradoxically causes a wide variety of injuries. Opening of mitochondrial permeability transition pore (mPTP) and Ca2+ overload contribute to myocardial ischemia-reperfusion (I/R) injury. We aimed to investigate the protective role of a novel necrosis inhibitor (NecroX-7; NecX) against myocardial I/R injury, using in vitro and in vivo models.
Methods and Results: In H9C2 rat cardiomyoblasts exposed to hypoxia-reoxygenation stress, the main mechanism of cell death was not apoptosis but necrosis, which was prevented mainly by NecX, the necrosis inhibitor, but not by Z-VAD-fmk, the apoptosis inhibitor. The protective effect of NecX was based on its potent ROS scavenging activity, especially on mitochondrial ROS which is one of the major inducers of mPTP opening. NecX preserved mitochondrial membrane potential, mitochondrial structure, through prevention of Ca2+ influx and inhibition of the opening of mPTP. Inhibition of necrosis by NecX was accompanied by reduction of phospho-p38 MAPK and phospho-JNK, and decrease of HMGB1. Using Sprague-Dawley rats exposed to myocardial ischemia for 45 minutes followed by reperfusion, we compared therapeutic efficacies of NecX and Ciclosporin A (CsA) with 5% dextrose (control), each administrated 5 minutes before reperfusion. NecX markedly inhibited myocardial necrosis, reduced fibrotic area and attenuated the release of cardiac enzymes, compared to dextrose and CsA. Additionally, NecX preserved systolic function and prevented pathologic dilatory remodeling of left ventricle.
Conclusion: The novel necrosis inhibitor has a significant protective effect against myocardial I/R injury, indicating that it is a promising candidate for cardioprotective adjunctive measure on top of reperfusion therapy.
Clinical implication: We are trying to translate this experimental data into patients. A phase I clinical trial confirmed the safety profiles of NecX [NCT01737424] and a phase II trial for STEMI patients (NEXsteMI trial) is ongoing [NCT02070471].
Author Disclosures: H. Cho: None. I. Hwang: None. J. Kim: None. H. Lee: None. J. Lee: None. J. Park: None. H. Yang: None. Y. Kwon: None. S. Kim: 1. Employment; Significant; Employee of LG Life Science. H. Kim: None.
- © 2015 by American Heart Association, Inc.