IL-4 as a Repurposed Biological Drug for Myocardial Infarction through Augmentation of Reparative Cardiac Macrophages: Proof-of-Concept Data in Mice.

Recent research has shown that reparative (alternatively activated or M2) macrophages play a role in repair of damaged tissues, including the infarcted hearts. Administration of IL-4 is known to augment M2 macrophages. This translational study thus aimed to investigate whether IL-4 administration is useful for the treatment of myocardial infarction. Long-acting IL-4 complex (IL-4c; recombinant IL-4 mixed with anti-IL-4 monoclonal antibody as a stabilizer) was administered after coronary artery ligation in mice. It was observed that IL-4c administration increased accumulation of CD206+F4/80+ M2-like macrophages predominantly in the injured myocardium, compared to the control. Sorted cardiac M2-like macrophages highly expressed wide-ranging tissue repair-related genes. Indeed, IL-4c administration enhanced cardiac function in association with reduced infarct size and enhanced tissue repair (strengthened connective tissue formation, improved microvascular formation and attenuated cardiomyocyte hypertrophy). Experiments using Trib1 -/- mice that had a depleted ability to develop M2 macrophages and other in-vitro studies supported that these IL-4-mediated effects were induced via M2-like macrophages. On the other hand, when administered at Day 28 post-MI, the effects of IL-4c were diminished, suggesting a time-frame for IL-4 treatment to be effective. These data represent proof-of-concept of efficacy of IL-4 treatment for acute myocardial infarction, encouraging its further development.This project was funded by the Heart Research UK Translational Research Grant (RG2653/15/16), British Heart Foundation Programme Grant (RG/15/31236), and Queen Mary Innovation Proof of Concept Grant (2015). The National Institute for Health Researchfunded Barts Cardiovascular Biomedical Research Unit also supported this project.This project was funded by the Heart Research UK Translational Research Grant (RG2653/15/16), British Heart Foundation Programme Grant (RG/15/31236), and Queen Mary Innovation Proof of Concept Grant (2015). The National Institute for Health Research-funded Barts Cardiovascular Biomedical Research Unit also supported this project

Nanoparticles for targeting the infarcted heart

Author's Manuscript: 2012 October 12.We report a nanoparticulate system capable of targeting the heart after myocardial infarction (MI). Targeting is based on overexpression of angiotensin II type 1 (AT1) receptor in the infarcted heart. Liposomes 142 nm in diameter were conjugated with a ligand specific to AT1. The nanoparticles were able to specifically target cardiac cells in vitro, and in the infarcted heart after intravenous injection in vivo. This system may be useful for delivering therapeutic agents specifically to the infarcted heart.National Institutes of Health (U.S.) (Grant EB000244)National Institutes of Health (U.S.) (Grant EB006365)National Institutes of Health (U.S.) (Grant HL 086967)National Institutes of Health (U.S.) (Grant GM073626)American Heart Association (Postdoctoral Fellowship)Misrock Foundation (Postdoctoral Fellowship