I-κB kinase-ε deficiency improves doxorubicin-induced dilated cardiomyopathy by inhibiting the NF-κB pathway

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, wild-type mice (WT, n = 14) and IKKε knockout mice (IKKε-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、IKKε-KO + Saline group and IKKε-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, IKKε-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 IKKε-KO mice, and the expression of cardiac gap junction proteins was much higher in IKKε-KO mice. Further testing found that pyroptosis and apoptosis in the 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 may be a potential target for the treatment of dilated cardiomyopathy in the future.

Sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents ejection fraction reduction, reduces myocardial and renal NF-κB expression and systemic pro-inflammatory biomarkers in models of short-term doxorubicin cardiotoxicity

“…Moreover, activation of NF-κB has been implicated in the inflammatory response and development of cardiac injuries ( 105 ); DOXO increases myocardial reactive oxygen species that can activate NF-κB signaling. Once activated, NF-κB translocates into the nucleus and promotes the expression of various pro-inflammatory genes, including cytokines, chemokines, and adhesion molecules involved in heart failure and fibrosis ( 106 ).…”

Sodium-glucose cotransporter 2 inhibitor Dapagliflozin prevents ejection fraction reduction, reduces myocardial and renal NF-κB expression and systemic pro-inflammatory biomarkers in models of short-term doxorubicin cardiotoxicity

“…Moreover, activation of NF-κB has been implicated in the in ammatory response and development of cardiac injuries [77]; DOXO increases myocardial reactive oxygen species that can activate NF-κB signalling. Once activated, NF-κB translocates into the nucleus and promotes the expression of various pro-in ammatory genes, including cytokines, chemokines, and adhesion molecules involved in heart failure and brosis [78].…”

CYP2J2-derived epoxyeicosatrienoic acids protect against doxorubicin-induced cardiotoxicity by reducing oxidative stress and apoptosis via activation of the AMPK pathway

“…Purified vectors of rAAV9-CYP2J2 (1 × 10 11 pfu) or rAAV9-GFP (1 × 10 11 pfu) were administered via the caudal vein [ 17 ]. Two weeks after rAAV9 injection, the mice were intraperitoneally injected with DOX (5 mg/kg/week) or the same volume of saline solution for five weeks [ 18 ]. All mice were weighed weekly and euthanized on seven days after the final dose of DOX.…”