Aims: Uncontrolled activation of pro-inflammatory macrophages after myocardial infarction (MI) accelerates adverse left ventricular (LV) remodeling and dysfunction. Hemin, an iron-containing porphyrin, activates heme oxygenase-1 (HO-1), an enzyme with anti-inflammatory and cytoprotective properties. We sought to determine the effects of hemin formulated in macrophage-targeted liposomes on LV remodeling and function after MI.
Methods And Results: We formulated hemin in hyaluronan liposomes (HA-L). Hemin encapsulation efficiency was ~100% at therapeutic dose levels. In vitro, hemin/HA-L abolished TNF-α secretion from macrophages, whereas the same doses of free hemin and drug-free liposomes had no effect. Notably, free hemin polarized peritoneal and splenic macrophages toward M2 anti-inflammatory cells. We next induced MI in mice and allocated them to IV treatment with hemin/HA-L (2mg/kg), empty liposomes, free hemin (2 mg/kg) or saline, one day after MI. Efficacy and specificity of infarct macrophage targeting was confirmed with HA-L loaded with rhodamine (Fig. 1). LV remodeling and function were assessed by echocardiography before and one week after treatment. Significantly, hemin/HA-L improved LV function, and attenuated LV remodeling (Fig 2) via HO-1 induction.
Conclusion: Macrophage-targeted liposomes with hemin switch macrophages into an anti-inflammatory phenotype, elevate HO-1 expression and improve cardiac remodeling and dysfunction after MI. Our approach presents a novel strategy to modulate inflammation and improve infarct repair in high-risk cardiac patients.
