Aims: Myocardial infarction (MI) is the most common cause of heart failure. Excessive production of reactive oxygen species plays a key role in the pathogenesis of cardiac remodeling after MI. NADPH with Nox2 as the catalytic subunit is a major source of superoxide production and expression is significantly increased in the infarcted myocardium, especially by infiltrating macrophages. While microRNAs (miRNAs) are potent regulators of gene expression, and play an important role in heart disease, there still lacks efficient ways to identify miRNAs that target important pathological genes for treating MI. Thus, the overall objective was to establish a miRNA screening and delivery system for improving heart function after MI using Nox2 as a critical target. Methods and Results: By utilizing the miRNA-target screening system comprised of a self-assembled cell microarray(SAMcell), three miRNAs, miR-106b, miR-148b, and miR-204, were identified that could regulate Nox2 expression and its downstream products both in human and mouse macrophages. Each of these miRNAs were encapsulated into polyketal (PK3) nanoparticles that could effectively deliver miRNAs into macrophages. Both in vitro and in vivo studies in mice confirmed the PK3-miRNAs particles could inhibit Nox2 expression and activity, and significantly improve infarct size and acute cardiac function after MI. Conclusions: Our results show that miR-106b, miR-148b and miR-204 were able to improve heart function after myocardial infarction in mice by targeting Nox2 and possibly altering inflammatory cytokine production. This screening system and delivery method could have broader implication for miRNA-mediated therapeutics for cardiovascular and other diseases.
- myocardial infarction
- oxidative stress
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology