Key result
MiR-155 inhibition reduces post-MI ventricular arrhythmias by decreasing macrophage-mediated IL-1β and MMP7 expression.
Why the study?
Pro-inflammatory macrophage-mediated Cx43 degradation promotes post-MI arrhythmogenesis, and macrophage-derived miR-155 mediates post-MI effects, prompting investigation into whether miR-155 inhibition attenuates Cx43 degradation.
Inhibition of miR-155 attenuates post-MI connexin 43 degradation and reduces ventricular arrhythmias by suppressing pro-inflammatory macrophage activation.
MiR-155 inhibition merits further preclinical testing for post-MI arrhythmias; leaves open clinical translation pending human studies.
Background: Degradation of pro-inflammatory macrophage-mediated connexin 43 (Cx43) plays an important role in post-myocardial infarction (MI) arrhythmogenesis, microRNA (miR)-155 produced by macrophages has been shown to mediate post-MI effects. We hypothesized that miR-155 inhibition attenuated MI-induced Cx43 degradation by reducing pro-inflammatory macrophage activation. Methods: models. qRT-PCR, Western-blot and immunofluorescence were used to analyze relevant indicators. Results: The expression levels of miR-155, interleukin-1 beta (IL-1β), and matrix metalloproteinase (MMP)7 were higher in MI mice and LPS-treated BMDMs than in the sham/control groups, treatment with a miR-155 antagomir reversed these effects. Moreover, miR-155 inhibition reduced ventricular arrhythmias incidence and improved cardiac function in MI mice. Cx43 expression was decreased in MI mice and hypoxia-exposed NRCMs, and hypoxia-induced Cx43 degradation in NRCMs was reduced by application of conditioned medium from LPS-induced BMDMs treated with the miR-155 antagomir, but increased by conditioned medium from BMDMs treated with a miR-155 agomir. Importantly, NRCMs cultured in conditioned medium from LPS-induced BMDMs transfected with small interfering RNA against IL-1β and MMP7 showed decreased hypoxia-mediated Cx43 degradation, and this effect also was diminished by BMDM treatment with the miR-155 agomir. Additionally, siRNA-mediated suppressor of cytokine signaling 1 (SOCS1) knockdown in LPS-induced BMDMs promoted Cx43 degradation in hypoxia-exposed NRCMs, and the effect was reduced by the miR-155 inhibition. Conclusions: MiR-155 inhibition attenuated post-MI Cx43 degradation by reducing macrophage-mediated IL-1β and MMP7 expression through the SOCS1/nuclear factor-κB pathway.
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Yang et al. (2022) studied Myocardial infarction. miR-155 antagomir vs. Sham/control was evaluated on Connexin 43 degradation, ventricular arrhythmias incidence, and cardiac function. MiR-155 inhibition attenuated post-myocardial infarction connexin 43 degradation and reduced ventricular arrhythmias by decreasing macrophage-mediated IL-1β and MMP7 expression.
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