Abstract 17181: ACE Inhibition prevents the Release of Monocytes from their Splenic Reservoir in Mice with Myocardial Infarction
Recent findings indicate that monocytes recruited to ischemic myocardium originate from a reservoir in the spleen, and that the release from the splenic niche relies on angiotensin-II (Ang-II) signaling. Since monocytes are centrally involved in tissue repair following ischemia, we hypothesized that early ACEi therapy, in addition to its known hemodynamic and local actions, impacts healing after myocardial infarction via effects on monocyte trafficking.
Methods and Results: In a mouse model of permanent coronary ligation, Enalapril arrested the release of monocytes from the splenic reservoir and consequently reduced their recruitment within the next 24 hours into the healing infarct by 45%, as quantified by flow cytometry. Time-lapse intravital microscopy revealed that Enalapril reduces monocyte motility in the spleen (p<0.05 vs no MI). In vitro migration assays and Western blotting showed that this was caused by reduced signaling through the Ang-II receptor subtype 1. We then studied the long-term consequences of blocked splenic monocyte release in atherosclerotic apoE−/− mice, in which infarct healing is impaired due to excessive inflammation in the cardiac wound. Short term Enalapril treatment improved histological healing biomarkers and reduced the number of monocytes in infarcts from 1.23±0.1 million in untreated to 0.35±0.1 million in Enalapril treated apoE−/− mice. In vivo Fluorescence molecular tomography (FMT-CT) revealed that ACEi resulted in marked reduction of proteolytic activity. Even though treatment was discontinued after 7 days, ACE inhibition improved MRI-derived ejection fraction by 14% on day 21 (p<0.05 vs control), despite initially comparable infarct size in the control group.
Conclusions: This study provides mechanistic insight into the effect of ACEi on monocyte trafficking. These data suggest that benefits of early ACE inhibition after MI can be partially attributed to its potent anti-inflammatory impact on the splenic monocyte reservoir.
- © 2010 by American Heart Association, Inc.