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

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, IFN γ 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 m etabolism 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‐e ffects.
Source: The Journal of Pathology - Category: Pathology Authors: Tags: Original Paper Source Type: research