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

Yide Cao,Zhonghao Tao,Yafeng Liu,Liangpeng Li,Rui Wang,Ganyi Chen,Wen Chen,Jun Gong

doi:10.1155/2021/6429197

Yide Cao, Zhonghao Tao + Show 6 more

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https://doi.org/10.1155/2021/6429197

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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.

Highlights

Heart failure is a growing public health problem and a leading cause of morbidity and mortality in modern society
We found an obvious increase in IKKε in WT mouse heart tissues after 8 weeks of continuous Angiotensin II (Ang II) infusion
The echocardiographic analysis of cardiac function showed a significant decrease in the ejection fraction (EF), fraction shortening (FS), and E/A, as well as an increase in the left ventricular posterior wall diastole (LVPWd) in WT mice after 8 weeks of Ang II infusion, which indicated the attenuation of myocardial hypertrophy and deterioration of LV function in IKKε-KO mice compared with those of WT mice (Figures 2(c) and 2(d))

Summary

Introduction

Heart failure is a growing public health problem and a leading cause of morbidity and mortality in modern society. Pathological cardiac hypertrophy induced by aging and neurohumoral activation (e.g., angiotensin II (Ang II)) is an independent risk factor for heart failure [1, 2]. Clinical and epidemiological studies have identified that cardiac hypertrophy is an important independent risk factor for the development of heart failure and malignant arrhythmia [3]. The multiple signaling mechanisms that control cardiomyocyte growth have been studied extensively, but the molecular mechanisms that mediate the development of cardiac hypertrophy and the transition to heart failure remain incompletely understood. I-κB kinases (IKKs) have been recognized as regulators of the NF-κB pathway. The IKK complex consists of IKKα, IKKβ, IKKγ, and IKKε. IKKβ and IKKα are key regulators of the classical and alternative NF-κB pathways, respectively.

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