Abstract 027: Therapeutic Potential of a Novel Necrosis Inhibitor in Myocardial Ischemia-Reperfusion Injury
Background: Reperfusion, although essential for salvage of myocardium in the myocardial infarction, paradoxically causes a wide variety of injuries. The opening of the mitochondrial permeability pore and Ca2+ overload contribute to myocardial ischemia-reperfusion (I/R) injury.
Objectives: Necrosis, the main mechanism of cell death during I/R injury to the myocardium, is an uncontrolled cell death, a pathologic condition accompanying inflammatory responses. We aimed to examine the protective role of this novel necrosis inhibitor against myocardial I/R injury using in vitro and in vivo models through anti-necrosis pathway.
Methods and Results: Rat cardiomyocytes were exposed to hypoxia-reoxygenation injury after pretreatment with dimethyl sulfoxide (vehicle), necrosis inhibitor (NecX), antioxidant (vitamin C) or apoptosis inhibitor (Z-VAD-fmk). NecX-treated cells, compared with vehicle, showed fewer necrosis (Annexin-V/PI) (13.5±1.9% versus 44.1±3.1%; P=0.049) and more viable cells (fluorescein diacetate) (98.0±0.5% versus 51.3±2.1%; P=0.021). We next analyzed the mechanisms of cell death, mitochondrial membrane potential and mitochondrial Ca2+ level. NecX-treated group showed higher mitochondrial membrane potential and lower Ca2+ level, resulting in the prevention of mitochondrial swelling and necrosis. In the rat model of myocardial ischemia for 45 minutes followed by reperfusion, we compared the therapeutic efficacy of NecX and cyclosporine A (CsA) with 5% dextrose (control), each administrated 5 minutes before reperfusion. Pretreatment with NecX markedly inhibited myocardial necrosis (NecX, 7.8±7.8%; control, 65.4±2.4%, P=0.017; CsA, 32.3±5.1%, P=0.041) and reduced the area of fibrosis (NecX, 4.8±0.9%; control, 25.7±1.6%, P=0.011; CsA, 18.8±1.3%, P=0.006). Additionally, it preserved systolic function and prevented pathologic remodeling of left ventricle.
Conclusion: The novel necrosis inhibitor demonstrates a significant protective effect against myocardial I/R injury and has advantages over CsA, based more on the direct necrosis inhibition on cardiomyocytes, indicating that it is a promising candidate for cardioprotective adjunctive therapy with reperfusion in patients with myocardial infarction.
- © 2013 by American Heart Association, Inc.