Neuregulin-1 Attenuates Myocardial Ischemia/Reperfusion Injury by Activating the UCP2/PINK1/LC3B-mediated Mitophagy

Avatar
Poster
Voice is AI-generated
Connected to paperThis paper is a preprint and has not been certified by peer review

Neuregulin-1 Attenuates Myocardial Ischemia/Reperfusion Injury by Activating the UCP2/PINK1/LC3B-mediated Mitophagy

Authors

Li, X.-T.; Li, X.-Y.; Tian, T.; Yang, W.-H.; Cheng, Y.; Su, K.; Lu, X.; Jin, M.; Xue, F.-S.

Abstract

BACKGROUND:Available evidence suggests that neuregulin-1(NRG-1) can provide a protection against myocardial ischemia/reperfusion(I/R) injury and is involved in various cardioprotective interventions by potential regulation of mitophagy. However, the molecular mechanisms linking NRG-1 and mitophagy remain to be clarified. This experiment aimed to determine whether NRG-1 postconditioning attenuated myocardial I/R injury through the regulation of mitophagy and to explore the underlying mechanisms. METHOD: Both an in vivo myocardial I/R injury model of rats and an in vitro hypoxia/reoxygenation(H/R) model of H9C2 cardiomyocytes were applied. NRG-1 treatment was conducted immediately after I/R or H/R intervention. In the in vivo experiment, cardioprotective effects of NRG-1 were determined by infarct size, cardiac enzyme and histopathologic examinations. The potential downstream pathways and molecular targets of NRG-1 were screened by the RNA sequencing and the Protein-Protein Interaction Networks(PPI). The expression levels of mitochondrial uncoupling protein 2(UCP2) and mitophagy-related protein in both the I/R myocardium and H/R cardiomyocytes were measured by immunofluorescence staining and Western blots. The activation of mitophagy was observed with the transmission electron microscopy (TEM) and JC-1 staining. RESULTS: The KEGG and GSEA analyses showed that the mitophagy-related pathways were enriched in the I/R myocardium treated with NRG-1, and UCP2 exhibited a significant correlation between mitophagy and interaction with PINK1. Meanwhile, the treatment with mitophagy inhibitor Mdivi-1 significant eliminated the cardioprotective effects of NRG-1 postconditioning in vivo, and the challenge with UCP2 inhibitor genipin could also attenuate the activating effect of NRG-1 postconditioning on mitophagy. Consistently, the in vitro experiment using H9C2 cardiomyocytes showed that NRG-1 treatment significantly up-regulated the expression levels of UCP2 and mitophagy-related proteins, and activated the mitophagy, whereas the challenge with small interfering RNA-mediated UCP2 knockdown abolished the effects of NRG-1. CONCLUSIONS: NRG-1 postconditioning can produce a protection against the myocardial I/R injury by activating mitophagy through the UCP2/PINK1/LC3B signaling pathway.

Follow Us on

0 comments

Add comment