Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction

Florian Leuschner, Peter Panizzi, Isabel Chico-Calero, Won Woo Lee, Takuya Ueno, Virna Cortez-Retamozo, Peter Waterman, Rostic Gorbatov, Brett Marinelli, Yoshiko Iwamoto, Aleksey Chudnovskiy, Jose Luiz Figueiredo, David E. Sosnovik, Mikael J. Pittet, Filip K. Swirski, Ralph Weissleder, Matthias Nahrendorf

Research output: Contribution to journalArticlepeer-review

188 Scopus citations

Abstract

Rationale: Monocytes recruited to ischemic myocardium originate from a reservoir in the spleen, and the release from their splenic niche relies on angiotensin (Ang) II signaling. Objective: Because monocytes are centrally involved in tissue repair after ischemia, we hypothesized that early angiotensin-converting enzyme (ACE) inhibitor therapy impacts healing after myocardial infarction partly via effects on monocyte traffic. 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 into the healing infarct by 45%, as quantified by flow cytometry of digested infarcts. Time-lapse intravital microscopy revealed that enalapril reduces monocyte motility in the spleen. In vitro migration assays and Western blotting showed that this was caused by reduced signaling through the Ang II type 1 receptor. We then studied the long-term consequences of blocked splenic monocyte release in atherosclerotic apolipoprotein (apo)E-/- mice, in which infarct healing is impaired because of excessive inflammation in the cardiac wound. Enalapril improved histologic healing biomarkers and reduced inflammation in infarcts measured by FMT-CT (fluorescence molecular tomography in conjunction with x-ray computed tomography) of proteolytic activity. ACE inhibition improved MRI-derived ejection fraction by 14% on day 21, despite initially comparable infarct size. In apoE-/- mice, ischemia/reperfusion injury resulted in larger infarct size and enhanced monocyte recruitment and was reversible by enalapril treatment. Splenectomy reproduced antiinflammatory effects of enalapril. Conclusion: This study suggests that benefits of early ACE inhibition after myocardial infarction can partially be attributed to its potent antiinflammatory impact on the splenic monocyte reservoir.

Original languageEnglish
Pages (from-to)1364-1373
Number of pages10
JournalCirculation Research
Volume107
Issue number11
DOIs
StatePublished - 26 Nov 2010
Externally publishedYes

Keywords

  • ACE inhibitor
  • Heart failure
  • Monocyte
  • Myocardial infarction
  • Spleen

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