Objective:Arsenic trioxide(ATO or As2O3)has beneficial effects on suppressing neointimal hyperplasia and restenosis,but the mechanism is still unclear.The goal of this study is to further understand the mechanism of A...Objective:Arsenic trioxide(ATO or As2O3)has beneficial effects on suppressing neointimal hyperplasia and restenosis,but the mechanism is still unclear.The goal of this study is to further understand the mechanism of ATO's inhibitory effect on vascular smooth muscle cells(VSMCs).Methods and results:Through in vitro cell culture and in vivo stent implanting into the carotid arteries of rabbit,a synthetic-to-contractile phenotypic transition was induced and the proliferation of VSMCs was inhibited by ATO.F-actin filaments were clustered and the elasticity modulus was increased within the phenotypic modulation of VSMCs induced by ATO in vitro.Meanwhile,Yes-associated protein(YAP)nuclear translocation was inhibited by ATO both in vivo and in vitro.It was found that ROCK inhibitor or YAP inactivator could partially mask the phenotype modulation of ATO on VSMCs.Conclusions:The interaction of YAP with the ROCK pathway through ATO seems to mediate the contractile phenotype of VSMCs.This provides an indication of the clinical therapeutic mechanism for the beneficial bioactive effect of ATO-drug eluting stent(AES)on in-stent restenosis(ISR).展开更多
Objective： To explore the effects of arsenic trioxide （ATO） on the apoptosis of glucocorticoid （GC）-resistant T-acute lymphoblastic leukemia （ALL） CEM-C1 cells and its possible mechanisms. Methods： Different ...Objective： To explore the effects of arsenic trioxide （ATO） on the apoptosis of glucocorticoid （GC）-resistant T-acute lymphoblastic leukemia （ALL） CEM-C1 cells and its possible mechanisms. Methods： Different concentrations of ATO （0.25 μmol/L-5 μmol/L） were used to induce the apoptosis of CEM-C1 cells. The inhibition rate of cell proliferation and apoptosis were detected by MTT test, Annexin V-FITC/PI flow cytometry and optical microscopy, respectively. RT-PCR was applied to semi-quantitatively analyze the mRNA expression of pro-apoptotic proteins （Bad and PDCD4） and anti-apoptotic proteins （XIAP and MCL-1） induced by different concentrations of ATO at different time points. Results： ATO could inhibit proliferation and induce apoptosis of CEM-C1 cells at a concentration and time dependent manner. Low-dose ATO mildly inhibited the proliferation of CEM-C1 cells while higher concentrations （1 μmol/L and 5 μmol/L） had strong anti-tumor effect with the inhibiting rates of 40.07±7.98% and 88.67±2.88%, respectively. Annexin V-FITC/PI flow cytometry showed that the apoptotic rates of CEM-C1 ceils were significantly increased after 48 hours treatment of different concentrations of ATO. RT-PCR demonstrated up-regulated mRNA expression of pro-apoptotic protein Bad and PDCD4 but down-regulated mRNA expression of anti-apoptotic protein XIAP when CEM-C1 cells were treated with different concentrations of ATO at different time points. The MCL-1 mRNA expression was down-regulated only after the treatment of 5 μmol/L ATO. Conclusion： ATO can inhibit cell proliferation and induce cell apoptosis in GC-resistant CEM-C1 cells. The molecular mechanisms might involve the increased mRNA expression of pro-apoptotic protein Bad and PDCD-4, and rapid down-regulation of XIAP mRNA expression.展开更多
基金This study was supported in part by grants from the National Natural Science Foundation of China,China(31971242,31701275)the National Science Foundation of Chongqing,China(cstc2020jcjymsxmX0189)+4 种基金the Chongqing Research Program of Basic Research and Frontier Technology,China(CSTC2019JCYJ-ZDXM0033)Open Fund for Key Laboratory of Biorheological Science and Technology,Ministry of Education,China(CQKLBST-2019-010)Innovation Talent Project of 2020 for Chongqing Primary and secondary School,China(CY200405)the National Key R&D Program,China(2016YFC1102305)The support from the Chongqing Engineering Laboratory in Vascular Implants,China,the Public Experiment Centre of State Bioindustrial Base(Chongqing)and the National“111 Plan”,China(B06023)are gratefully acknowledged.
文摘Objective:Arsenic trioxide(ATO or As2O3)has beneficial effects on suppressing neointimal hyperplasia and restenosis,but the mechanism is still unclear.The goal of this study is to further understand the mechanism of ATO's inhibitory effect on vascular smooth muscle cells(VSMCs).Methods and results:Through in vitro cell culture and in vivo stent implanting into the carotid arteries of rabbit,a synthetic-to-contractile phenotypic transition was induced and the proliferation of VSMCs was inhibited by ATO.F-actin filaments were clustered and the elasticity modulus was increased within the phenotypic modulation of VSMCs induced by ATO in vitro.Meanwhile,Yes-associated protein(YAP)nuclear translocation was inhibited by ATO both in vivo and in vitro.It was found that ROCK inhibitor or YAP inactivator could partially mask the phenotype modulation of ATO on VSMCs.Conclusions:The interaction of YAP with the ROCK pathway through ATO seems to mediate the contractile phenotype of VSMCs.This provides an indication of the clinical therapeutic mechanism for the beneficial bioactive effect of ATO-drug eluting stent(AES)on in-stent restenosis(ISR).
基金supported by a grant from the Science and Technology Committee of Sichuan Province (No2008JY0029-1)
文摘Objective： To explore the effects of arsenic trioxide （ATO） on the apoptosis of glucocorticoid （GC）-resistant T-acute lymphoblastic leukemia （ALL） CEM-C1 cells and its possible mechanisms. Methods： Different concentrations of ATO （0.25 μmol/L-5 μmol/L） were used to induce the apoptosis of CEM-C1 cells. The inhibition rate of cell proliferation and apoptosis were detected by MTT test, Annexin V-FITC/PI flow cytometry and optical microscopy, respectively. RT-PCR was applied to semi-quantitatively analyze the mRNA expression of pro-apoptotic proteins （Bad and PDCD4） and anti-apoptotic proteins （XIAP and MCL-1） induced by different concentrations of ATO at different time points. Results： ATO could inhibit proliferation and induce apoptosis of CEM-C1 cells at a concentration and time dependent manner. Low-dose ATO mildly inhibited the proliferation of CEM-C1 cells while higher concentrations （1 μmol/L and 5 μmol/L） had strong anti-tumor effect with the inhibiting rates of 40.07±7.98% and 88.67±2.88%, respectively. Annexin V-FITC/PI flow cytometry showed that the apoptotic rates of CEM-C1 ceils were significantly increased after 48 hours treatment of different concentrations of ATO. RT-PCR demonstrated up-regulated mRNA expression of pro-apoptotic protein Bad and PDCD4 but down-regulated mRNA expression of anti-apoptotic protein XIAP when CEM-C1 cells were treated with different concentrations of ATO at different time points. The MCL-1 mRNA expression was down-regulated only after the treatment of 5 μmol/L ATO. Conclusion： ATO can inhibit cell proliferation and induce cell apoptosis in GC-resistant CEM-C1 cells. The molecular mechanisms might involve the increased mRNA expression of pro-apoptotic protein Bad and PDCD-4, and rapid down-regulation of XIAP mRNA expression.
