I-κB kinase-ε knockout protects against angiotensin II induced aortic valve thickening in apolipoprotein E deficient mice

Yao

et al. 2022

Front. Physiol.

Self Cite

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.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Yao

et al. 2022

Front. Physiol.

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“…Additionally, the IKKε is a non-canonical IκB kinase that plays a signi cant role in brosis and in ammation (8,24). Previous studies (15,25) Dilated cardiomyopathy is often accompanied by arrhythmia. IKKε knockout is a primary therapeutic strategy for reducing brosis because the heart electrophysiology can be disrupted by brotic tissue and triggered life-threatening arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of NF-κB-dependent transcription has been found in numerous heart diseases, including hypertrophic cardiomyopathy, myocardial infarction, ischemia/reperfusion injury, and so on (7,(11)(12)(13)(14). In our previous studies, the role in atherosclerotic lesions and aortic stenosis has been suggested (15,16). However, The role of IKKε in dilated cardiomyopathy is unclear.…”

Section: Introductionmentioning

confidence: 96%

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

Xu²,

Yao

et al. 2022

Preprint

Self Cite

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.

I‐κB Kinase‐ε Deficiency Attenuates the Development of Angiotensin II‐Induced Myocardial Hypertrophy in Mice

Cao

Oxidative Medicine and Cellular Longevity

et al. 2021

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I-κB kinase-ε (IKKε) is a member of the IKK complex and a proinflammatory regulator that is active in many diseases. Angiotensin II (Ang II) is a vasoconstricting peptide hormone, and Ang II-induced myocardial hypertrophy is a common cardiovascular disease that can result in heart failure. In this study, we sought to determine the role of IKKε in the development of Ang II-induced myocardial hypertrophy in mice. Wild-type (WT) and IKKε-knockout (IKKε-KO) mice were generated and infused with saline or Ang II for 8 weeks. We found that WT mouse hearts have increased IKKε expression after 8 weeks of Ang II infusion. Our results further indicated that IKKε-KO mice have attenuated myocardial hypertrophy and alleviated heart failure compared with WT mice. Additionally, Ang II-induced expression of proinflammatory and collagen factors was much lower in the IKKε-KO mice than in the WT mice. Apoptosis and pyroptosis were also ameliorated in IKKε-KO mice. Mechanistically, IKKε bound to extracellular signal-regulated kinase (ERK) and the mitogen-activated protein kinase p38, resulting in MAPK/ERK kinase (MEK) phosphorylation, and IKKε deficiency inhibited the phosphorylation of MEK-ERK1/2 and p38 in mouse heart tissues after 8 weeks of Ang II infusion. The findings of our study reveal that IKKε plays an important role in the development of Ang II-induced myocardial hypertrophy and may represent a potential therapeutic target for the management of myocardial hypertrophy.