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

Abstract

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.

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

“…Activation of NF-κB–dependent transcription has been found in numerous heart diseases, including hypertrophic cardiomyopathy, myocardial infarction, ischemia/reperfusion injury, and so on ( Jones et al, 2005 ; Hall et al, 2006 ; Baldwin, 2012 ; Kumar et al, 2012 ; Maier et al, 2012 ; Cao et al, 2021 ). In our previous studies, the role of IKKε in atherosclerotic lesions and aortic stenosis has been suggested ( Cao et al, 2013 ; He et al, 2019 ).…”

“…In our previous studies, the role of IKKε in atherosclerotic lesions and aortic stenosis has been suggested ( Cao et al, 2013 ; He et al, 2019 ). The IKKε-KO could attenuate mice’s pathological progression in Angiotensin II-Induced Myocardial Hypertrophy and aortic valve thickening ( He et al, 2019 ; Cao et al, 2021 ). However, the role of IKKε in dilated cardiomyopathy is unclear.…”