Abstract 14909: Hydrogen Peroxide-Responsive Nanoparticles Reduce Myocardial Ischemia/Reperfusion Injury

Abstract

During myocardial ischemia/reperfusion (I/R), a large amount of reactive oxygen species (ROS) is produced which causes oxidative stress and leads to severe cellular and tissue damage. In particular, overproduction of hydrogen peroxide (H2O2) is considered as a main cause of I/R-mediated tissue damage by inducing inflammation and apoptosis. Therefore, rapid elimination of H2O2 and suppression of oxidative stress are thought to be reasonable strategies to treat myocardial I/R injury. Recently, we generated novel H2O2-responsive antioxidant polymer nanoparticles (PVAX and HPOX) that are able to target the site of ROS overproduction and impede the progression of oxidative stress-associated diseases. In this study, PVAX nanoparticles were selected as therapeutic agents for myocardial I/R injury based on the results of direct comparison studies in vitro and in vivo. To explore therapeutic effect of PVAX on cardiac I/R injury, cardiac function 2 weeks after reperfusion was evaluated. A single dose of PVAX (3mg/kg) showed a significant improvement in both cardiac output (8.1± 0.7 vs. 3.4±0.3) and fraction shortening (43.8± 0.9 vs. 31.2±3.8) compared with poly (lactic-co-glycolic acid) (PLGA) particle, a lacking H2O2 responsible nanoparticle. Consistent with cardiac function evaluation, PVAX significantly reduced the myocardial infarction /area at risk compared with PLGA (48.7±4.2 vs.14.5±2.1). In addition, PVAX effectively reduced caspase-3 activation (2.6±0.1 vs.1.4±0.1) and TUNEL-positive cells (8.2±1.8 vs. 2.7±0.6) compared with PLGA. Furthermore, PVAX significantly decreased TNF-α (5.5±0.4 vs. 3.0±0.3) and MCP-1 (2.3±0.1 vs. 1.4±0.1) mRNA levels. To explore the antioxidant effect of PVAX by scavenging ROS, dihydroethidium (DHE) staining was used as an indicator of ROS generation. PVAX effectively suppressed the generation of ROS caused by I/R while a number of DHE-positive cells were observed in a group of PLGA I/R. In addition, PVAX significantly reduced the level of NADPH oxidase (NOX) 2 and 4 expression, which favors the reduction in ROS generation after I/R. Taken together, these results suggest that H2O2-responsive antioxidant PVAX has tremendous potential as a therapeutic agent for myocardial I/R injury.