RESUMO
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).
Assuntos
Macrófagos/efeitos dos fármacos , MicroRNAs/antagonistas & inibidores , Infarto do Miocárdio/patologia , Plasticidade Neuronal/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia , Animais , Antagomirs/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Fator de Crescimento Neural/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
Endoplasmic reticulum stress (ERS)-induced cardiomyocyte apoptosis plays an important role in the pathological process following myocardial infarction (MI). Macrophages that express microRNA-155 (miR-155) mediate cardiac inflammation, fibrosis, and hypertrophy. Therefore, we investigated if miR-155 regulates ERS-induced cardiomyocyte apoptosis after MI using a mouse model, lipopolysaccharide (LPS)-induced rat bone marrow derived macrophages (BMDMs)and hypoxia-induced neonatal rat cardiomyocytes (NRCMs). In vivo, miR-155 levelswere significantly higher in the MI group compared to the sham group. MI increasedmacrophage infiltration, nuclear factor-κB (NF-κB) activation, ERS induced-apoptosis, and SOCS1 expression, all of which were attenuated by the miR-155 antagomir, with the exception of SOCS1 expression. Additionally, post-MI cardiac dysfunction was significantly improved by miR-155 inhibition. In vitro, LPS upregulated miR-155 expression in BMDMs, and the miR-155 antagomir decreased LPS-induced macrophage inflammation and NF-κB pathway activation, but increased expression of SOCS1. Hypoxia increased NF-κB pathway activation, ERS marker expression, and apoptosis in NRCMs. Interestingly, conditioned medium from LPS-induced macrophages in combination with the miR-155 antagomir decreased, while the miR-155 agomir increased, the hypoxia-induced effects in NRCM's. The miR-155 agomir effects were reversed by inhibiting the NF-κB pathway in cardiomyocytes. Moreover, SOCS1 knockdown in LPS-induced macrophages promoted NF-κB pathway activation and ERS-induced cardiomyocyte apoptosis in the hypoxia-induced NRCMs, but the SOCS1-siRNA-induced effects were markedly decreased by miR-155 antagomir treatment. These data suggest that miR-155 inhibition attenuates ERS-induced cardiomyocyte apoptosis after MI via reducing macrophage inflammation through the SOCS1/NF-κB pathway.