Doxorubicin-induced cardiotoxicity involves IFNγ-mediated metabolic reprogramming in cardiomyocytes

Immune responses contribute to a large extent to heart diseases. However, it is still not clear how the key inflammatory mediator interferon-gamma (IFN gamma) plays a role in doxorubicin (DOX)-induced cardiomyopathy. We report here that DOX-induced heart dysfunction involves IFN gamma signaling in mice. The IFN gamma receptor was found to be highly expressed on cardiomyocytes, and its downstream signaling was activated in heart tissues upon DOX treatment. In vitro, IFN gamma strongly aggravated the injury of cardiomyocytes exposed to DOX. Although not affecting DOX-induced cell death, IFN gamma disrupted mitochondrial respiration and fatty acid oxidation in DOX-exposed cardiomyocytes. IFN gamma extended the suppression of the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) axis by DOX to a p38-dependent branch. Activation of AMPK or inhibition of p38 inhibited the enhancing effect of IFN gamma on the DOX-induced cardiotoxicity and prolonged the survival time in DOX-treated mice. Taken together, our results indicate that reprogramming of cardiac metabolism by IFN gamma represents a previously unidentified key step for DOX-induced cardiomyopathy. This unavoidable impact of IFN gamma on cardiomyocyte metabolism during chemotherapy redirects our attention to the balance between beneficial immunosurveillance of cancer cells and unwanted toxic side-effects. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.