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Leukocyte immunoglobulin-like receptor B4 protects against cardiac hypertrophy via SHP-2-dependent inhibition of the NF-κB pathway

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Abstract

Cardiac hypertrophy is a complex pathological process, and the molecular mechanisms underlying hypertrophic remodeling have not been clearly elucidated. Leukocyte immunoglobulin-like receptor B4 (lilrb4) is an inhibitory transmembrane protein that is necessary for the regulation of various cellular signaling pathways. To investigate whether lilrb4 plays a role in cardiac hypertrophy, we performed aortic banding in lilrb4 knockout mice, lilrb4 cardiac-specific transgenic mice, and their wild-type littermates. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. We found that lilrb4 was expressed both in myocardial tissue and on cultured cardiomyocytes under basal conditions, but the expression was obviously decreased in mouse hearts following aortic banding and in cardiomyocytes treated with angiotensin II. Lilrb4 disruption aggravated cardiac hypertrophy, fibrosis, and dysfunction in response to pressure overload. Conversely, the cardiac overexpression of lilrb4 led to the opposite effects. Moreover, lilrb4 overexpression inhibited angiotensin II-induced cardiomyocyte hypertrophy in vitro. Mechanistically, we determined that the cardioprotective effect of lilrb4 was mediated through an interaction with SHP-2, the preservation of phosphorylated SHP-2, and the inhibition of the NF-κB pathway. In addition, SHP-2 knockdown in cardiomyocytes eliminated the inhibitory effects of lilrb4 on angiotensin II-induced hypertrophy and NF-κB activation. Our results suggest that lilrb4 protects against pathological cardiac hypertrophy via the SHP-2-dependent inhibition of the NF-κB pathway and may act as a potential therapeutic target for cardiac hypertrophy.

Key messages

  • Lilrb4 expression is decreased by hypertrophic stimuli.

  • Lilrb4 protects against pathological cardiac hypertrophy.

  • Lilrb4 interacts with SHP-2 and inhibits NF-κB pathway.

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Acknowledgments

We thank Dr. Toshiyuki Takai (Tohoku University) for generously providing the lilrb4 knockout mice.

Funding

This work was supported by the National Natural Science Foundation of China (81770399, 81300070, 81530012 and 81700218), the Fundamental Research Funds for the Central Universities of China (2042018kf0121 and 2042018kf1032), National Key R&D Program of China (2018YFC1311300), Development Center for Medical Science and Technology National Health and Family Planning Commission of the People’s Republic of China (The prevention and control project of cardiovascular disease, 2016ZX-008-01), the National Natural Science Foundation of Hubei Province (2017CFB320).

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Authors and Affiliations

  1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China

    Heng Zhou, Ning Li, Yuan Yuan, Ya-Ge Jin, Qingqing Wu, Ling Yan, Zhou-Yan Bian, Wei Deng, Di-Fei Shen, Hongliang Li & Qi-Zhu Tang

  2. Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, 430060, People’s Republic of China

    Heng Zhou, Ning Li, Yuan Yuan, Ya-Ge Jin, Qingqing Wu, Ling Yan, Zhou-Yan Bian, Wei Deng, Di-Fei Shen, Hongliang Li & Qi-Zhu Tang

  3. Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, People’s Republic of China

    Heng Zhou, Ning Li, Yuan Yuan, Ya-Ge Jin, Qingqing Wu, Ling Yan, Zhou-Yan Bian, Wei Deng, Di-Fei Shen, Hongliang Li & Qi-Zhu Tang

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  1. Heng Zhou
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Zhou, H., Li, N., Yuan, Y. et al. Leukocyte immunoglobulin-like receptor B4 protects against cardiac hypertrophy via SHP-2-dependent inhibition of the NF-κB pathway. J Mol Med 98, 691–705 (2020). https://doi.org/10.1007/s00109-020-01896-w

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