Growth differentiation factor 11 mitigates cardiac radiotoxicity via activating AMPKα

Cardiac radiotoxicity largely impedes the therapeutic benefits of radiotherapy to malignancies. Growth differentiation factor 11 (GDF11) is implicated in the pathogenesis of cardiac diseases under different pathological conditions. This study aims to investigate the role and underlying mechanisms of GDF11 on cardiac radiotoxicity. Mice were injected with cardiotropic adeno-associated virus 9 carrying the full-length mouse GDF11 gene or negative control under a cTnT promoter from the tail vein, and then received a single dose of 20 Gray (Gy) whole-heart irradiation (WHI) for 16 weeks to imitate cardiac radiotoxicity. Compound C (CC, 20 mg/kg) was intraperitoneally injected every two days at 1 week before WHI stimulation to inhibit 5′ AMP-activated protein kinase α (AMPKα). Cardiac GDF11 expression was significantly suppressed at both the protein and mRNA levels. GDF11 overexpression decreased oxidative stress, apoptosis, and fibrosis in radiated hearts, thereby mitigating cardiac radiotoxicity, and dysfunction. Further detection revealed that GDF11 activated AMPKα to reduce radiation-induced oxidative damage and that AMPKα inhibition by CC offset the cardioprotective effects by GDF11. GDF11 mitigates cardiac radiotoxicity via activating AMPKα and it is a promising candidate to treat cardiac radiotoxicity.