I-?B kinase-e deficiency improves doxorubicin-induced dilated cardiomyopathy by inhibiting the NF-?B pathway

Dilated cardiomyopathy (DCM) can lead to heart expansion and severe heart failure, but its specific pathogenesis is still elusive. In many cardiovascular diseases, I-kappa B kinase-epsilon (IKK epsilon) has been recognized as a pro-inflammatory molecule. In this study, wild-type mice (WT, n = 14) and IKK epsilon knockout mice (IKK epsilon-KO, n = 14) were intraperitoneally injected with a cumulative dose of 25 mg/kg with Dox or Saline five times in 30 days. Finally, the experimental mice were divided into WT + Saline group?WT + DOX group?IKK epsilon-KO + Saline group and IKK epsilon-KO + Dox group. Echocardiography was performed to assess cardiac structure and function. Moreover, the mechanism was validated by immunohistochemistry and western blotting. Our results demonstrated that compared to WT + Dox mice, IKK epsilon-KO + Dox mice exhibited attenuation of dilated cardiomyopathy-related morphological changes and alleviation of heart failure. Additionally, compared to the WT mice after Dox-injected, the expression of fibrosis and proinflammatory were decreased in IKK epsilon-KO mice, and the expression of cardiac gap junction proteins was much higher in IKK epsilon-KO mice. Further testing found that pyroptosis and apoptosis in the myocardium were also ameliorated in IKK epsilon-KO mice compared to WT mice after Dox was injected. Mechanistically, our results showed that deficiency of IKK epsilon might inhibit the phosphorylation of I kappa B alpha, p65, RelB, and p100 in mouse heart tissues after Dox stimulation. In summary, our research suggests that IKK epsilon might play an essential role in the development of Dox-induced dilated cardiomyopathy and may be a potential target for the treatment of dilated cardiomyopathy in the future.