Mechanical Regulation of Macrophage Metabolism by Allograft Inflammatory Factor 1 Leads to Adverse Remodeling After Cardiac Injury

Authors

Matthew DeBerge
Kristofor Glinton
Connor Lantz
Zhi-Dong Ge
David P Sullivan
Swapna Patil
Bo Ryung Lee
Minori I Thorp
Adam Mullick
Steve Yeh
Shuling Han
Anja M van der Laan
Hans W M Niessen
Xunrong Luo
Nicholas E S Sibinga
Edward B Thorp

Language

English

Publication Date

1-1-2025

Journal

Nature Cardiovascular Research

DOI

10.1038/s44161-024-00585-y

PMID

39747455

PMCID

PMC12665373

PubMedCentral® Posted Date

12-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Myocardial infarction (MI) mobilizes macrophages, the central protagonists of tissue repair in the infarcted heart. Although necessary for repair, macrophages also contribute to adverse remodeling and progression to heart failure. In this context, specific targeting of inflammatory macrophage activation may attenuate maladaptive responses and enhance cardiac repair. Allograft inflammatory factor 1 (AIF1) is a macrophage-specific protein expressed in a variety of inflammatory settings, but its function after MI is unknown. Here we identify a maladaptive role for macrophage AIF1 after MI in mice. Mechanistic studies show that AIF1 increases actin remodeling in macrophages to promote reactive oxygen species-dependent activation of hypoxia-inducible factor (HIF)-1α. This directs a switch to glycolytic metabolism to fuel macrophage-mediated inflammation, adverse ventricular remodeling and progression to heart failure. Targeted knockdown of Aif1 using antisense oligonucleotides improved cardiac repair, supporting further exploration of macrophage AIF1 as a therapeutic target after MI.

Keywords

Animals, Macrophages, Myocardial Infarction, Microfilament Proteins, Ventricular Remodeling, Mice, Inbred C57BL, Calcium-Binding Proteins, Reactive Oxygen Species, Disease Models, Animal, Hypoxia-Inducible Factor 1, alpha Subunit, Glycolysis, Heart Failure, Male, Signal Transduction, Mice, Myocardium, Ventricular Function, Left, Macrophage Activation, Actins, DNA-Binding Proteins, Humans

Published Open-Access

yes

Recommended Citation

DeBerge, Matthew; Glinton, Kristofor; Lantz, Connor; et al., "Mechanical Regulation of Macrophage Metabolism by Allograft Inflammatory Factor 1 Leads to Adverse Remodeling After Cardiac Injury" (2025). Faculty, Staff and Student Publications. 5523.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5523