Leukocyte immunoglobulin-like receptor B4 protects against cardiac hypertrophy via SHP-2-dependent inhibition of the NF-κB pathway
- 12 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Molecular Medicine
- Vol. 98 (5), 691-705
- https://doi.org/10.1007/s00109-020-01896-w
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.Keywords
Funding Information
- National Natural Science Foundation of China (81300070, 81770399, 81530012, 81700218)
- Fundamental Research Funds for the Central Universities (2042018kf0121, 2042018kf1032)
- Key Technologies Research and Development Program (2018YFC1311300)
- National Health and Family Planning Commission of the People's Republic of China (2016ZX-008-01)
- Natural Science Foundation of Hubei Province (2017CFB320)
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