Targeting deubiquitinase OTUB1 protects vascular smooth muscle cells in atherosclerosis by modulating PDGFRβ

Atherosclerosis is a chronic artery disease that causes various types of cardiovascular dysfunction.Vascular smooth muscle cells(VSMCs),the main components of atherosclerotic plaque,switch from contractile to synthetic phenotypes during atherogenesis.Ubiquitylation is crucial in regulating VSMC phenotypes in atherosclerosis,and it can be reversely regulated by deubiquitinases.However,the specific effects of deubiquitinases on atherosclerosis have not been thoroughly elucidated.In this study,RNAi screening in human aortic smooth muscle cells was performed to explore the effects of OTU family deubiquitinases,which revealed that silencing OTUB1 inhibited PDGF-BB-stimulated VSMC phenotype switch.Further in vivo studies using Apoe−/−mice revealed that knockdown of OTUB1 in VSMCs alleviated atherosclerosis plaque burden in the advanced stage and led to a stable plaque phenotype.Moreover,VSMC proliferation and migration upon PDGF-BB stimulation could be inhibited by silencing OTUB1 in vitro.Unbiased RNA-sequencing data indicated that knocking down OTUB1 influenced VSMC differentiation,adhesion,and proliferation.Mass spectrometry of ubiquitinated protein confirmed that proteins related to cell growth and migration were differentially ubiquitylated.Mechanistically,we found that OTUB1 recognized the K707 residue ubiquitylation of PDGFRβwith its catalytic triad,thereby reducing the K48-linked ubiquitylation of PDGFRβ.Inhibiting OTUB1 in VSMCs could promote PDGFRβdegradation via the ubiquitin–proteasome pathway,so it was beneficial in preventing VSMCs’phenotype switch.These findings revealed that knocking down OTUB1 ameliorated VSMCs’phenotype switch and atherosclerosis progression,indicating that OTUB1 could be a valuable translational therapeutic target in the future.

Impact of the gut microbiome on atherosclerosis

Atherosclerosis is a chronic inflammatory metabolic disease with a complex pathogenesis.However,the exact details of its pathogenesis are still unclear,which limits effective clinical treatment of atherosclerosis.Recently,multiple studies have demonstrated that the gut microbiota plays a pivotal role in the onset and progression of atherosclerosis.This review discusses possible treatments for atherosclerosis using the gut microbiome as an intervention target and summarizes the role of the gut microbiome and its metabolites in the development of atherosclerosis.New strategies for the treatment of atherosclerosis are needed.This review provides clues for further research on the mechanisms of the relationship between the gut microbiota and atherosclerosis.

A TEMPOL and rapamycin loaded nanofiber-covered stent favors endothelialization and mitigates neointimal hyperplasia and local inflammation

An increased level of reactive oxygen species(ROS)plays a major role in endothelial dysfunction and vascular smooth muscle cell(VSMC)proliferation during in-stent thrombosis and restenosis after coronary artery stenting.Herein,we report an electrospun core-shell nanofiber coloaded with 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl(TEMPOL)and rapamycin(RAPA)that correspondingly serves as an ROS scavenger and VSMC inhibitor.This system has the potential to improve the biocompatibility of current drug-eluting stent(DES)coatings with the long-term and continuous release of TEMPOL and rapamycin.Moreover,the RAPA/TEMPOL-loaded membrane selectively inhibited the proliferation of VSMCs while sparing endothelial cells(ECs).This membrane demonstrated superior ROS-scavenging,anti-inflammatory and antithrombogenic effects in ECs.In addition,the membrane could maintain the contractile phenotype and mitigate platelet-derived growth factor BB(PDGF-BB)-induced proliferation of VSMCs.In vivo results further revealed that the RAPA/TEMPOL-loaded covered stents promoted rapid restoration of vascular endothelium compared with DES and persistently impeded inflammation and neointimal hyperplasia in porcine models.