Azithromycin therapy reduces cardiac inflammation and mitigates adverse cardiac remodeling after myocardial infarction: Potential therapeutic targets in ischemic heart disease

Ahmed Al-Darraji, Dalia Haydar, Lakshman Chelvarajan, Himi Tripathi, Bryana Levitan, Erhe Gao, Vincent J. Venditto, John C. Gensel, David J. Feola, Ahmed Abdel-Latif

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30 Scopus citations

Abstract

Introduction Acute myocardial infarction (MI) is a primary cause of worldwide morbidity and mortality. Macrophages are fundamental components of post-MI inflammation. Pro-inflammatory macrophages can lead to adverse cardiac remodeling and heart failure while anti-inflammatory/reparative macrophages enhance tissue healing. Shifting the balance between pro-inflammatory and reparative macrophages post-MI is a novel therapeutic strategy. Azithromycin (AZM), a commonly used macrolide antibiotic, polarizes macrophages towards the anti-inflammatory phenotype, as shown in animal and human studies. We hypothesized that AZM modulates post-MI inflammation and improves cardiac recovery. Methods and results Male WT mice (C57BL/6, 6–8 weeks old) were treated with either oral AZM (160 mg/kg/day) or vehicle (control) starting 3 days prior to MI and continued to day 7 post-MI. We observed a significant reduction in mortality with AZM therapy. AZM-treated mice showed a significant decrease in pro-inflammatory (CD45+/Ly6G-/F4-80+/CD86+) and increase in anti-inflammatory (CD45+/Ly6G-/F4-80+/CD206+) macrophages, decreasing the pro-inflammatory/anti-inflammatory macrophage ratio in the heart and peripheral blood as assessed by flow cytometry and immunohistochemistry. Macrophage changes were associated with a significant decline in pro- and increase in anti-inflammatory cytokines. Mechanistic studies confirmed the ability of AZM to shift macrophage response towards an anti-inflammatory state under hypoxia/reperfusion stress. Additionally, AZM treatment was associated with a distinct decrease in neutrophil count due to apoptosis, a known signal for shifting macrophages towards the anti-inflammatory phenotype. Finally, AZM treatment improved cardiac recovery, scar size, and angiogenesis. Conclusion Azithromycin plays a cardioprotective role in the early phase post-MI through attenuating inflammation and enhancing cardiac recovery. Post-MI treatment and human translational studies are warranted to examine the therapeutic applications of AZM.

Original languageEnglish
Article numbere0200474
JournalPLoS ONE
Volume13
Issue number7
DOIs
StatePublished - Jul 2018

Bibliographical note

Funding Information:
Dr. Abdel-Latif is supported by the National Heart, Lung, and Blood Institute (P20 GM103527) and the NIH Grant R01 HL124266. This work is supported by National Heart, Lung, and Blood Institute, P30 CA177558. The flow cytometry core facility is supported by the grant P30 CA177558. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We are grateful for Jennifer Simkin for her assistance with the immunohistochemistry studies.

Publisher Copyright:
© 2018 Al-Darraji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ASJC Scopus subject areas

  • General

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