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Doxorubicin-induced cardiotoxicity involves IFNγ-mediated metabolic reprogramming in cardiomyocytes.
Journal of Pathology 2018 November 15
Immune responses contribute to a large extent to heart diseases. However, it is still not clear how the key inflammatory mediator Interferon-γ (IFNγ) plays a role in doxorubicin (DOX)-induced cardiomyopathy. We report here that DOX-induced heart dysfunction involves IFNγ signaling in mice. The IFNγ receptor was found to be highly expressed on cardiomyocytes, and its downstream signaling was activated in heart tissues upon DOX treatment. In vitro, IFNγ strongly aggravated the injury of cardiomyocytes exposed to DOX. Although not affecting DOX-induced cell death, IFNγ disrupted mitochondrial respiration and fatty acid oxidation in DOX-exposed cardiomyocytes. IFNγ 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 IFNγ 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 IFNγ represents a previously unidentified key step for DOX-induced cardiomyopathy. This unavoidable impact of IFNγ on cardiomyocyte metabolism during chemotherapy redirects our attention to the balance between beneficial immunosurveillance of cancer cells and unwanted toxic side-effects.
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