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 syntheti...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.展开更多
The commercially available drug-eluting stent with limus (rapamycin, everolimus, etc.) or paclitaxel inhibits smooth muscle cell (SMC), reducing the in-stent restenosis, whereas damages endothelial cell (EC) and delay...The commercially available drug-eluting stent with limus (rapamycin, everolimus, etc.) or paclitaxel inhibits smooth muscle cell (SMC), reducing the in-stent restenosis, whereas damages endothelial cell (EC) and delays stent reendothelialization, increasing the risk of stent thrombosis (ST) and sudden cardiac death. Here we present a new strategy for promoting stent reendothelialization and preventing ST by exploring the application of precise molecular targets with EC specificity. Proteomics was used to investigate the molecular mechanism of EC injury caused by rapamycin. Endothelial protein C receptor (EPCR) was screened out as a crucial EC-specific effector. Limus and paclitaxel repressed the EPCR expression, while overexpression of EPCR protected EC from coating (eluting) drug-induced injury. Furthermore, the ligand activated protein C (APC), polypeptide TR47, and compound parmodulin 2, which activated the target EPCR, promoted EC functions and inhibited platelet or neutrophil adhesion, and enhanced rapamycin stent reendothelialization in the simulated stent environment and in vitro. In vivo, the APC/rapamycin-coating promoted reendothelialization rapidly and prevented ST more effectively than rapamycin-coating alone, in both traditional metal stents and biodegradable stents. Additionally, overexpression or activation of the target EPCR did not affect the cellular behavior of SMC or the inhibitory effect of rapamycin on SMC. In conclusion, EPCR is a promising therapeutical agonistic target for pro-reendothelialization and anti-thrombosis of eluting stent. Activation of EPCR protects against coating drugs-induced EC injury, inflammatory cell, or platelet adhesion onto the stent. The novel application formula for APC/rapamycin-combined eluting promotes stent reendothelialization and prevents ST.展开更多
We propose and demonstrate an optical phased-array-based bidirectional grating antenna(BDGA) in silicon nitride waveguides.The BDGA is integrated with a miniaturized all-dielectric metasurface doublet(MD) formed on a ...We propose and demonstrate an optical phased-array-based bidirectional grating antenna(BDGA) in silicon nitride waveguides.The BDGA is integrated with a miniaturized all-dielectric metasurface doublet(MD) formed on a glass substrate.The BDGA device,which takes advantage of alternately feeding light to its ports in opposite directions,is presumed to effectively provide a doubled wavelength-tuned steering efficiency compared to its unidirectional counterpart.The MD,which is based on vertically cascaded convex and concave metalenses comprising circular hydrogenated amorphous silicon nanopillars,is meticulously placed atop the BDGA chip to accept and deflect a beam emanating from the emission area,thereby boosting the beam-steering performance.The manufactured BDGA could achieve an enhanced beam-steering efficiency of 0.148 deg/nm as well as a stable spectral emission response in the wavelength range of 1530–1600 nm.By deploying a fabricated MD atop the silicon photonic BDGA chip,the steering efficiency was confirmed to be boosted by a factor of ~3.1,reaching 0.461 deg/nm,as intended.展开更多
基金supported by grants from the National Key R&D Program of China(No.2021YFC2500500)the National Natural Science Foundation of China(Nos.T2288101 and 82170342)+1 种基金Shanghai Engineering Research Center of Interventional Medicine(No.19DZ2250300)Shanghai Clinical Research Center for Interventional Medicine(No.19MC1910300).
文摘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.
基金National Natural Science Foundation of China(82170413,82170342,82200377)Guangdong Basic and Applied Basic Research Foundation(2021A1515012546,2022A1515012474)+3 种基金Shanghai Yangfan Project(21YF1440000)Innovation Team of General Universities in Guangdong Province(2023KCXTD025)Guangzhou Science and Technology Plan(202102010101,202201020220)Student Innovation Program of Guangzhou Medical University(to S.J.L.).
文摘The commercially available drug-eluting stent with limus (rapamycin, everolimus, etc.) or paclitaxel inhibits smooth muscle cell (SMC), reducing the in-stent restenosis, whereas damages endothelial cell (EC) and delays stent reendothelialization, increasing the risk of stent thrombosis (ST) and sudden cardiac death. Here we present a new strategy for promoting stent reendothelialization and preventing ST by exploring the application of precise molecular targets with EC specificity. Proteomics was used to investigate the molecular mechanism of EC injury caused by rapamycin. Endothelial protein C receptor (EPCR) was screened out as a crucial EC-specific effector. Limus and paclitaxel repressed the EPCR expression, while overexpression of EPCR protected EC from coating (eluting) drug-induced injury. Furthermore, the ligand activated protein C (APC), polypeptide TR47, and compound parmodulin 2, which activated the target EPCR, promoted EC functions and inhibited platelet or neutrophil adhesion, and enhanced rapamycin stent reendothelialization in the simulated stent environment and in vitro. In vivo, the APC/rapamycin-coating promoted reendothelialization rapidly and prevented ST more effectively than rapamycin-coating alone, in both traditional metal stents and biodegradable stents. Additionally, overexpression or activation of the target EPCR did not affect the cellular behavior of SMC or the inhibitory effect of rapamycin on SMC. In conclusion, EPCR is a promising therapeutical agonistic target for pro-reendothelialization and anti-thrombosis of eluting stent. Activation of EPCR protects against coating drugs-induced EC injury, inflammatory cell, or platelet adhesion onto the stent. The novel application formula for APC/rapamycin-combined eluting promotes stent reendothelialization and prevents ST.
基金National Research Foundation of Korea(2018R1A6A1A03025242)Ministry of Science and ICT,Republic of Korea (2020R1A2C3007007)Kwangwoon University。
文摘We propose and demonstrate an optical phased-array-based bidirectional grating antenna(BDGA) in silicon nitride waveguides.The BDGA is integrated with a miniaturized all-dielectric metasurface doublet(MD) formed on a glass substrate.The BDGA device,which takes advantage of alternately feeding light to its ports in opposite directions,is presumed to effectively provide a doubled wavelength-tuned steering efficiency compared to its unidirectional counterpart.The MD,which is based on vertically cascaded convex and concave metalenses comprising circular hydrogenated amorphous silicon nanopillars,is meticulously placed atop the BDGA chip to accept and deflect a beam emanating from the emission area,thereby boosting the beam-steering performance.The manufactured BDGA could achieve an enhanced beam-steering efficiency of 0.148 deg/nm as well as a stable spectral emission response in the wavelength range of 1530–1600 nm.By deploying a fabricated MD atop the silicon photonic BDGA chip,the steering efficiency was confirmed to be boosted by a factor of ~3.1,reaching 0.461 deg/nm,as intended.
