Aims: Autophagy is an important cellular process for maintaining physiological homeostasis and is known to protect against cardiovascular diseases including ischemia reperfusion (I/R) injury. The underlying mechanisms behind its protection require further characterization.
Materials and methods: Atg7 knock out (AKO) mice were generated and subjected to I/R injury, complemented by Atg7 KO in a H9c2 cardiomyoblast cellular model ± hypoxia-reoxygenation. Subsequently, in both models, inflammation and cell death were studied.
Key findings: We confirmed that Atg7 KO led to autophagy, including mitophagy, deficiency. Upon H/R, Atg7 KO cells exhibited increased cell death compared to WT cells. Notably, we found that autophagy deficiency increased stress-induced mitochondrial fission, release of mitochondrial DNA, and sterile inflammation, namely activation of a STING/IRF3 axis leading to elevated interferon-α. Following I/R injury, AKO mice showed elevated cell death which correlated with a gene expression profile indicative of decreased anti-inflammatory responses.
Significance: Autophagy deficiency in the cardiomyocyte setting results in detrimental effects during I/R injury in mice or H/R injury in cells, mediated in part via mtDNA/IRF3/STING pathway. As such, modulation of this pathway may yield novel and promising therapeutics to treat or prevent I/R injury.
Keywords: Atg7; Autophagy; Cell death; Heart; Hypoxia; Reoxygenation.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.