Inhibition of microRNA-155 attenuates sympathetic neural remodeling following myocardial infarction via reducing M1 macrophage polarization and inflammatory responses in mice

Inflammation plays an important role in sympathetic neural remodeling induced by myocardial infarction (MI). MiR-155 is a vital regulator of inflammatory responses, and macrophage-secreted miR-155 promotes cardiac fibrosis and hypertrophy. However, whether miR-155 influences MI-induced sympathetic n...

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Bibliographic Details
Published in:European journal of pharmacology 2019-05, Vol.851, p.122-132
Main Authors: Hu, Juan, Huang, Cong-Xin, Rao, Pan-Pan, Zhou, Ji-Peng, Wang, Xi, Tang, Lu, Liu, Ming-Xin, Zhang, Guo-Gang
Format: Article
Language:English
Subjects:
Animals
Antagomirs - pharmacology
Gene Expression Regulation - drug effects
Inflammation - genetics
Inflammation - pathology
Inflammation - physiopathology
Macrophage
Macrophages - cytology
Macrophages - drug effects
Male
Mice
Mice, Inbred C57BL
MicroRNAs - antagonists & inhibitors
MiR-155
Myocardial infarction
Myocardial Infarction - genetics
Myocardial Infarction - metabolism
Myocardial Infarction - pathology
Myocardial Infarction - physiopathology
Nerve growth factor
Nerve Growth Factor - metabolism
Neuronal Plasticity - drug effects
Suppressor of Cytokine Signaling 1 Protein - metabolism
Sympathetic Nervous System - drug effects
Sympathetic Nervous System - physiopathology
Sympathetic neural remodeling
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Summary:Inflammation plays an important role in sympathetic neural remodeling induced by myocardial infarction (MI). MiR-155 is a vital regulator of inflammatory responses, and macrophage-secreted miR-155 promotes cardiac fibrosis and hypertrophy. However, whether miR-155 influences MI-induced sympathetic neural remodeling is not clear. Therefore, we examined the role of miR-155 in MI-induced sympathetic neural remodeling and the related mechanisms in both an mouse model and in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs). Our data showed that miR-155 expression was significantly enhanced in the myocardial tissues of MI mice compared to sham mice. Also, MI up-regulated the electrophysiological parameters, M1 macrophage polarization, inflammatory responses, and suppressor of cytokine signaling 1 (SOCS1) expression, which coincided with the increased expression of sympathetic nerve remodeling markers(nerve growth factor, tyrosine hydroxylase and growth-associated protein 43). Except for SOCS1, these proteins were attenuated by miR-155 antagomir. In vitro, LPS-stimulation promoted miR-155 expression in BMDMs. Consistent with the in vivo findings, miR-155 antagomir diminished the LPS-induced M1 macrophage polarization, nuclear factor (NF)-κB activation, and the expression of pro-inflammatory factors and nerve growth factor; but it increased the expression of SOCS1. Inversely, miR-155 agomir significantly potentiated LPS-induced pathophysiological effects in BMDMs. MiR-155 agomir-induced effects were reversed by the NF-κB inhibitor. Mechanistically, treatment with siRNA against SOCS1 augmented the aforementioned LPS-mediated activities, which were antagonized by the addition of miR-155 antagomir. In conclusion, miR-155 inhibition downregulated NGF expression via decreasing M1 macrophage polarization and inflammatory responses dependent on the SOCS1/NF-κB pathway, subsequently diminishing MI-induced sympathetic neural remodeling and ventricular arrhythmias (VAs).
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2019.02.001