Abstract GS107: Nil10: A Newly Synthesized Nanoparticle That Reduces Inflammation And Preserves Heart Function In Murine And Porcine Models Of Acute Myocardial Infarction

Abstract

Introduction: Interleukin-10 (IL-10) has long been recognized as a key anti-inflammatory cytokine, whose expression is associated to macrophage polarization towards resolution after acute myocardial infarction. Hypothesis: Targeting the IL10 receptor (IL10R) in patients undergoing AMI, may represent a new strategy to improve cardiac function. Methods and Results: We synthesized NIL10, a micelle-based nanoparticle conjugated to an IL-10 agonist, to analyze the effect on cardiac function and inflammation resolution after cardiac ischemia/reperfusion. After confirmation of NIL10 (conjugated with Rhodamine) co-localization to IL-10R, as detected by immunohistofluorescence (Fig. 1A), intravenous administration of 1 mg/kg NIL10 in mice and pigs subjected to AMI, efficiently decreased left ventricle fibrosis and significantly improved left ventricle ejection fraction (LVEF), by day 7 after injection, when compared to animals injected with, NIL10SC, a nanoparticle control (Fig. 1B-C). As expected, NIL10 induced macrophage polarization towards M2-like macrophages after day 3 of reperfusion (Fig D), by at least promoting IL-10R activity, as shown by increased phosphorylation of IL-10R and the downstream STAT3 in the necrotic area of the heart (Figure 1E). STAT3-dependent inflammation inhibition was assayed by administration of 50μM NIL10 in RAW-247 cells stimulated with 500 μM LPS, in which nuclear translocation of NF-κB was significantly reduced (Fig. 1E) by at least phosphorylation of I-κB-α. Conclusions: Our findings show NIL10 as a new tool to improve cardiac function in hearts under AMI, at least through inhibition of STAT3-induced nuclear translocation of NF-κB.