Abstract 15490: NIL10: A Novel Nanotechnological Compound to Prevent Monocyte Infiltration and Adverse Cardiac Remodeling in a Porcine Model of Myocardial Ischaemia-Reperfusion

Abstract

Introduction: Adverse cardiac remodeling following acute myocardial infarction (AMI) depends on how promptly the phagocytic-nuclear system responds. Among strategies to limit the inflammatory response, we have developed a nanoparticle (NIL10) which binds to IL-10 receptor (IL-10R) in-vitro and promotes macrophage polarization towards a resolutive phenotype in animal models of myocardial ischemia-reperfusion (I/R). However, its therapeutic use still depends on understanding its ability to regulate monocyte recruitment. Hypothesis: Targeting the IL-10R in circulating monocytes may represent a new therapeutic approach to improve cardiac function in patients undergoing AMI. Objective: To explore the molecular mechanisms leading to the inhibition of monocyte recruitment by NIL10 in pigs undergoing cardiac I/R. Methods: By using a porcine model of myocardial I/R, we arranged the following groups: (1) control group (2) intravenous administration (IV) 1 mg/kg NIL10, (3) IV of 4x10 5 isolated monocytes from group 2, (4) IV of 4x10 5 isolated monocytes from group 1 and then incubated with NIL10 (A). Results: Groups 2-4 exhibited better cardiac function compared to group 1 (B), which resulted in a decrease in myocardial fibrosis (C), along with a reduction of circulating CCR2+ monocytes (D) and a decrease in classical-monocyte infiltration, as shown by a reduction of CCR2+ macrophages in the necrotic area of the heart (E). As a result, CCL2 plasma expression, a functional ligand of CCR2, was decreased by day 7 post-I/R (F) in contrast to the necrotic tissue expression profile in which we detected large amounts of CCL2 (G) and STAT3 activation, indicative of IL10R activity (H). Conclusion: In addition to macrophage polarization, NIL10 induces cardiac protection by limiting classical monocyte infiltration after myocardial I/R, which opens a new window for using, in combination with endogenous monocyte therapy, to treat AMI.