lncR-GAS5 upregulates the splicing factor SRSF10 to impair endothelial autophagy,leading to atherogenesis

Long noncoding RNAs(lncRNAs)play a critical role in the regulation of atherosclerosis.Here,we investigated the role of the lncRNA growth arrest-specific 5(lncR-GAS5)in atherogenesis.We found that the enforced expression of lncR-GAS5 contributed to the development of atherosclerosis,which presented as increased plaque size and reduced collagen content.Moreover,impaired autophagy was observed,as shown by a decreased LC3II/LC3I protein ratio and an elevated P62 level in lncR-GAS5-overexpressing human aortic endothelial cells.By contrast,lncR-GAS5 knockdown promoted autophagy.Moreover,serine/arginine-rich splicing factor 10(SRSF10)knockdown increased the LC3II/LC3I ratio and decreased the P62 level,thus enhancing the formation of autophagic vacuoles,autolysosomes,and autophagosomes.Mechanistically,lncR-GAS5 regulated the downstream splicing factor SRSF10 to impair autophagy in the endothelium,which was reversed by the knockdown of SRSF10.Further results revealed that overexpression of the lncR-GAS5-targeted gene miR-193-5p promoted autophagy and autophagic vacuole accumulation by repressing its direct target gene,SRSF10.Notably,miR-193-5p overexpression decreased plaque size and increased collagen content.Altogether,these findings demonstrate that lncR-GAS5 partially contributes to atherogenesis and plaque instability by impairing endothelial autophagy.In conclusion,lncR-GAS5 overexpression arrested endothelial autophagy through the miR-193-5p/SRSF10 signaling pathway.Thus,miR-193-5p/SRSF10 may serve as a novel treatment target for atherosclerosis.

Berberine prevents primary peritoneal adhesion and adhesion reformation by directly inhibiting TIMP-1

Peritoneal adhesions are fibrous tissues that tether organs to one another or to the peritoneal wall and represent the major cause of postsurgical morbidity.Enterolysis at repeat surgeries induces adhesion reformation that is more difficult to prevent than primary adhesion.Here we studied the preventive effects of different approaches of berberine treatment for primary adhesion,and its effects on adhesion reformation compared to Interceed.We found the primary adhesion was remarkably prevented by berberine through intraperitoneal injection 30 min before abrasive surgery(pre-berberine)or direct addition into injured cecum immediately after the surgery(inter-berberine).Rats with adhesion reformation had a more deteriorative collagen accumulation and tissue injury in abrasive sites than rats with primary adhesion.The dysregulated TIMP-1/MMP balance was observed in patients after surgery,as well as adhesion tissues from primary adhesion or adhesion reformation rats.Inter-berberine treatment had a better effect for adhesion reformation prevention than Interceed.Berberine promoted the activation of MMP-3 and MMP-8 by directly blocking TIMP-1 activation core,which was reversed by TIMP-1 overexpression in fibroblasts.In conclusion,this study suggests berberine as a reasonable approach for preventing primary adhesion formation and adhesion reformation.