Azithromycin Therapy Reduces Cardiac Inflammation and Mitigates Adverse Cardiac Remodeling After Myocardial Infarction: Potential Therapeutic Targets in Ischemic Heart Disease

Authors

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

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.

Document Type

Article

Publication Date

7-12-2018

Notes/Citation Information

Published in PLOS ONE, v. 13, no. 7, e0200474, p. 1-25.

© 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.

Digital Object Identifier (DOI)

https://doi.org/10.1371/journal.pone.0200474

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.

Related Content

All relevant data are within the paper and its Supporting Information files.

S1 Table. Forward and reverse primer sequence used in the experiments. https://doi.org/10.1371/journal.pone.0200474.s001 (DOCX)

S2 Table. Echocardiographic morphometric parameters at 30 days post-myocardial infarction. https://doi.org/10.1371/journal.pone.0200474.s002 (DOCX)

S1 Fig. AZM does not alter kidney or liver function with prolonged use after myocardial infarction. https://doi.org/10.1371/journal.pone.0200474.s003 (EPS)

S2 Fig. AZM treatment reduces IL-1β and increases YM1 expression in the peri-infarct border of the injured heart. https://doi.org/10.1371/journal.pone.0200474.s004 (EPS)

S3 Fig. AZM therapy reduces the secreted inflammatory cytokines. https://doi.org/10.1371/journal.pone.0200474.s005 (EPS)

S4 Fig. AZM reduces apoptosis in the infarcted heart. https://doi.org/10.1371/journal.pone.0200474.s006 (EPS)

Repository Citation

Al-Darraji, Ahmed; Haydar, Dalia; Chelvarajan, Lakshman; Tripathi, Himi; Levitan, Bryana R.; Gao, Erhe; Venditto, Vincent J.; Gensel, John C.; Feola, David James; and Abdel-Latif, Ahmed, "Azithromycin Therapy Reduces Cardiac Inflammation and Mitigates Adverse Cardiac Remodeling After Myocardial Infarction: Potential Therapeutic Targets in Ischemic Heart Disease" (2018). Gill Heart & Vascular Institute Faculty Publications. 16.
https://uknowledge.uky.edu/heart_facpub/16