Xue, F.-S. | Search bioRxiv

bioRxiv2024

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

BACKGROUNDIschemia/reperfusion (I/R) injury may significantly affect the treatment outcomes and prognosis of patients with acute myocardial infarction following coronary artery recanalization. Available evidence suggests that neuregulin-1 (NRG-1) can provide a protection against myocardial 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. METHODBoth 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. RESULTSThe 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 showd 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 (siRNA)-mediated UCP2 knockdown abolished the effects of NRG-1. CONCLUSIONSNRG-1 postconditioning can produce a protection against the myocardial I/R injury by activating mitophagy through the UCP2/PINK1/LC3B signaling pathway.

molecular biology↗

bioRxiv2022

Partial reuse of circadian clock genes along parallel clines of diapause in two moth species

Understanding the molecular basis of repeated evolution is essential for improving our ability to predict evolution. Genes repeatedly used in independent cases of adaptation to similar environments are strong candidates for predicting adaptation across phylogeny. The Asian corn borer (Ostrinia furnacalis; ACB) and the European corn borer (Ostrinia nubilalis; ECB) are two closely related moths that display remarkable adaptability to a wide range of climate on two separate continents, largely manifesting as changes in the timing of diapause (dormancy), but the genetic basis of parallel clinal responses remains to be characterized. We extensively sampled the ACB cline in China in a genome-wide association study (GWAS) using pooled sequencing data (Pool-seq). We characterized the genetic basis of clinal diapause response in ACB and showed that genes involved in circadian rhythm were over-represented among the candidate genes under spatially varying selection. Comparing with previous results from ECB, we found that the circadian clock gene period (per), but not pigment-dispersing factor receptor (Pdfr), was repeatedly used, but the alleles were not shared between the species. The corn borers shared adaptability is likely based in per but seemingly through independent mutational paths.

evolutionary biology↗