| First Author | Ni C | Year | 2019 |
| Journal | J Pathol | Volume | 247 |
| Issue | 3 | Pages | 320-332 |
| PubMed ID | 30426505 | Mgi Jnum | J:270191 |
| Mgi Id | MGI:6277345 | Doi | 10.1002/path.5192 |
| Citation | Ni C, et al. (2019) Doxorubicin-induced cardiotoxicity involves IFNgamma-mediated metabolic reprogramming in cardiomyocytes. J Pathol 247(3):320-332 |
| abstractText | Immune responses contribute to a large extent to heart diseases. However, it is still not clear how the key inflammatory mediator interferon-gamma (IFNgamma) plays a role in doxorubicin (DOX)-induced cardiomyopathy. We report here that DOX-induced heart dysfunction involves IFNgamma signaling in mice. The IFNgamma receptor was found to be highly expressed on cardiomyocytes, and its downstream signaling was activated in heart tissues upon DOX treatment. In vitro, IFNgamma strongly aggravated the injury of cardiomyocytes exposed to DOX. Although not affecting DOX-induced cell death, IFNgamma disrupted mitochondrial respiration and fatty acid oxidation in DOX-exposed cardiomyocytes. IFNgamma 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 IFNgamma 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 IFNgamma represents a previously unidentified key step for DOX-induced cardiomyopathy. This unavoidable impact of IFNgamma 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. |
