PMID- 35800355 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20221104 IS - 2223-3652 (Print) IS - 2223-3660 (Electronic) IS - 2223-3652 (Linking) VI - 12 IP - 3 DP - 2022 Jun TI - MicroRNA-155 inhibition attenuates myocardial infarction-induced connexin 43 degradation in cardiomyocytes by reducing pro-inflammatory macrophage activation. PG - 325-339 LID - 10.21037/cdt-21-743 [doi] AB - 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: MI was induced by permanent ligation of the left anterior descending coronary artery in male C57BL/6 mice. Lipopolysaccharide (LPS)-stimulated mice bone marrow-derived macrophages (BMDMs) and hypoxia-induced neonatal rat cardiomyocytes (NRCMs) were used in vitro models. qRT-PCR, Western-blot and immunofluorescence were used to analyze relevant indicators. RESULTS: The expression levels of miR-155, interleukin-1 beta (IL-1beta), 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-1beta 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-1beta and MMP7 expression through the SOCS1/nuclear factor-kappaB pathway. CI - 2022 Cardiovascular Diagnosis and Therapy. All rights reserved. FAU - Yang, Hai-Tao AU - Yang HT AD - Heart Center of Henan Provincial People's Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China. FAU - Li, Li-Li AU - Li LL AD - Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China. FAU - Li, Song-Nan AU - Li SN AD - Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China. FAU - Wu, Jin-Tao AU - Wu JT AD - Heart Center of Henan Provincial People's Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China. FAU - Chen, Ke AU - Chen K AD - Heart Center of Henan Provincial People's Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China. FAU - Song, Wei-Feng AU - Song WF AD - Heart Center of Henan Provincial People's Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China. FAU - Zhang, Guo-Bao AU - Zhang GB AD - Heart Center of Henan Provincial People's Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China. FAU - Ma, Ji-Fang AU - Ma JF AD - Heart Center of Henan Provincial People's Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China. FAU - Fu, Hai-Xia AU - Fu HX AD - Heart Center of Henan Provincial People's Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China. FAU - Cao, Sheng AU - Cao S AD - Department of Ultrasound, Renmin Hospital of Wuhan University, Wuhan, China. FAU - Gao, Chuan-Yu AU - Gao CY AD - Heart Center of Henan Provincial People's Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China. FAU - Hu, Juan AU - Hu J AD - Heart Center of Henan Provincial People's Hospital, Central China Fuwai Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou, China. LA - eng PT - Journal Article PL - China TA - Cardiovasc Diagn Ther JT - Cardiovascular diagnosis and therapy JID - 101601613 EIN - Cardiovasc Diagn Ther. 2022 Oct;12(5):756-757. PMID: 36329960 PMC - PMC9253173 OTO - NOTNLM OT - Myocardial infarction (MI) OT - connexin 43 (Cx43) OT - microRNA-155 (miR-55) OT - ventricular arrhythmias COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-21-743/coif). All authors report that this work was supported by the Joint Construction Project of Medical Science and Technology of Henan Province (Grant Nos. LHGJ20200072, LHGJ20200071 and LHGJ20200077) and the Medical Science and Technology Project of Henan Province (No. SBGJ202002030). The authors have no other conflicts of interest to declare. EDAT- 2022/07/09 06:00 MHDA- 2022/07/09 06:01 PMCR- 2022/06/01 CRDT- 2022/07/08 02:49 PHST- 2021/12/01 00:00 [received] PHST- 2022/06/01 00:00 [accepted] PHST- 2022/07/08 02:49 [entrez] PHST- 2022/07/09 06:00 [pubmed] PHST- 2022/07/09 06:01 [medline] PHST- 2022/06/01 00:00 [pmc-release] AID - cdt-12-03-325 [pii] AID - 10.21037/cdt-21-743 [doi] PST - ppublish SO - Cardiovasc Diagn Ther. 2022 Jun;12(3):325-339. doi: 10.21037/cdt-21-743.