I-κB kinase-ε deficiency attenuates the development of Doxorubicin-induced dilated cardiomyopathy

Abstract

Dilated cardiomyopathy (DCM) can lead to heart expansion and severe heart failure, but its specific pathogenesis is still elusive. In many cardiovascular diseases, I-κB kinase-ε (IKKε) has been recognized as a pro-inflammatory molecule. In this study, we aimed to determine the effect of IKKε on Dox-induced cardiomyopathy in mice. Wild-type mice (WT, n=14) and IKKε knockout mice (IKKε-KO, n=14) were generated and intraperitoneally injected with Dox or Saline five times in 30 days. Our results demonstrated that compared to WT mice, IKKε-KO mice exhibited attenuation of dilated cardiomyopathy-related morphological changes and alleviation of heart failure after Dox was injected.Additionally, compared to the WT mice after Dox-injected, the expression of fibrosis and proinflammatory were decreased in IKKε-KO mice, and the expression of cardiac gap junction proteins were much higher in IKKε-KO mice. Further testing found that pyroptosis and apoptosis in myocardium were also ameliorated in IKKε-KO mice compared to WT mice after Dox was injected. Mechanistically, our results showed that deficiency of IKKε might inhibit the phosphorylation of IκBα, p65, RelB ,and p100 in mouse heart tissues after Dox stimulation. In summary, our research suggests that IKKε might play an essential role in the development of Dox-induced dilated cardiomyopathy and maybe a potential target for the treatment of dilated cardiomyopathy in the future.