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Smooth muscle cell-specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia.

平滑肌细胞特异性纤维连接蛋白-EDA 介导表型转换和新生内膜增生。

  • 影响因子:10.49
  • DOI:10.1172/JCI124708
  • 作者列表:"Jain M","Dhanesha N","Doddapattar P","Chorawala MR","Nayak MK","Cornelissen A","Guo L","Finn AV","Lentz SR","Chauhan AK
  • 发表时间:2020-01-02
Abstract

:Fibronectin-splice variant containing extra domain A (Fn-EDA) is associated with smooth muscle cells (SMCs) following vascular injury. The role of SMC-derived Fn-EDA in SMC phenotypic switching or its implication in neointimal hyperplasia remains unclear. Herein, using human coronary artery sections with a bare metal stent, we demonstrate the expression of Fn-EDA in the vicinity of SMC-rich neointima and peri-strut areas. In mice, Fn-EDA colocalizes with SMCs in the neointima of injured carotid arteries and promotes neointima formation in the comorbid condition of hyperlipidemia by potentiating SMC proliferation and migration. No sex-based differences were observed. Mechanistic studies suggested that Fn-EDA mediates integrin- and TLR4-dependent proliferation and migration through activation of FAK/Src and Akt1/mTOR signaling, respectively. Specific deletion of Fn-EDA in SMCs, but not in endothelial cells, reduced intimal hyperplasia and suppressed the SMC synthetic phenotype concomitant with decreased Akt1/mTOR signaling. Targeting Fn-EDA in human aortic SMCs suppressed the synthetic phenotype and downregulated Akt1/mTOR signaling. These results reveal that SMC-derived Fn-EDA potentiates phenotypic switching in human and mouse aortic SMCs and neointimal hyperplasia in the mouse. We suggest that targeting Fn-EDA could be explored as a potential therapeutic strategy to reduce neointimal hyperplasia.

摘要

: 含有额外结构域 A (Fn-EDA) 的纤维连接蛋白剪接变异体与血管损伤后的平滑肌细胞 (SMCs) 相关。SMC 来源的 Fn-EDA 在 SMC 表型转换中的作用或其在新生内膜增生中的意义仍不清楚。在此,使用裸金属支架的人冠状动脉切片,我们证明了 Fn-EDA 在富含 SMC 的新生内膜和支撑周围区域的表达。在小鼠中,Fn-EDA 在损伤的颈动脉新生内膜中与 SMCs 共定位,并通过增强 SMC 增殖和迁移促进高脂血症共病条件下的新生内膜形成。未观察到基于性别的差异。机制研究表明,Fn-EDA 分别通过激活 FAK/Src 和 Akt1/mTOR 信号介导整合素和 TLR4-dependent 的增殖和迁移。SMCs 中 Fn-EDA 的特异性缺失,而内皮细胞中不特异性缺失,可减少内膜增生,抑制 SMC 合成表型,同时伴随 Akt1/mTOR 信号减少。靶向人主动脉 SMCs 中的 Fn-EDA 抑制合成表型,下调 Akt1/mTOR 信号。这些结果揭示了 SMC 来源的 Fn-EDA 增强了人和小鼠主动脉 SMCs 的表型转换和小鼠新生内膜增生。我们建议可以探索靶向 Fn-EDA 作为减少新生内膜增生的潜在治疗策略。

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发表时间:2020-01-01
来源期刊:Thrombosis research
DOI:10.1016/j.thromres.2019.11.016
作者列表:["Palmerini T","Barozzi C","Tomasi L","Riva DD","Marengo M","Cicoria G","Bruno AG","Bacchi-Reggiani ML","Naldi M","Bartolini M","Fanti S","Galiè N","Stone GW"]

METHODS:Aims : We sought to investigate the thrombogenicity of different DES and BMS in an in vitro system of stent perfusion. Material and Methods: The experimental model consisted of a peristaltic pump connected to 4 parallel silicone tubes in which different stents were deployed. Blood was drawn from healthy volunteers and the amount of stent surfaced -induced thrombus deposition was determined using 125 I -fibrinogen. Results: Compared to Resolute, Biomatrix and Vision, Xience was associated with the lowest amount of stent surface -induced thrombus formation, with a significant difference compared to Vision (125 I -fibrinogen median value deposition [IQ range]: 50 ng [25 -98] versus 560 ng [320 - 1,520], respectively, p<0.05), but not to other DES. In the second set of experiments Fluoropolymer -coated BMS not eluting drug was associated with a significant 3 -fold reduction in 125 I -fibrinogen deposition (245 ng [80 -300]) compared to Vision (625 ng [320 -760], p<0.05), but a 7 -fold increase compared to Xience (35 ng [20 -60], p<0.05). Finally Xience was associated with a significantly greater absorption of albumin compared to BMS. Conclusions: In an in vitro system of stent perfusion, Xience was associated with the lowest amount of stent surface -induced thrombus formation compared with Resolute, Biomatrix and Vision, with a noted synergistic effect between the fluoropolymer and the drug.

翻译标题与摘要 下载文献
影响因子:10.49
发表时间:2020-01-02
DOI:10.1172/JCI124708
作者列表:["Jain M","Dhanesha N","Doddapattar P","Chorawala MR","Nayak MK","Cornelissen A","Guo L","Finn AV","Lentz SR","Chauhan AK"]

METHODS::Fibronectin-splice variant containing extra domain A (Fn-EDA) is associated with smooth muscle cells (SMCs) following vascular injury. The role of SMC-derived Fn-EDA in SMC phenotypic switching or its implication in neointimal hyperplasia remains unclear. Herein, using human coronary artery sections with a bare metal stent, we demonstrate the expression of Fn-EDA in the vicinity of SMC-rich neointima and peri-strut areas. In mice, Fn-EDA colocalizes with SMCs in the neointima of injured carotid arteries and promotes neointima formation in the comorbid condition of hyperlipidemia by potentiating SMC proliferation and migration. No sex-based differences were observed. Mechanistic studies suggested that Fn-EDA mediates integrin- and TLR4-dependent proliferation and migration through activation of FAK/Src and Akt1/mTOR signaling, respectively. Specific deletion of Fn-EDA in SMCs, but not in endothelial cells, reduced intimal hyperplasia and suppressed the SMC synthetic phenotype concomitant with decreased Akt1/mTOR signaling. Targeting Fn-EDA in human aortic SMCs suppressed the synthetic phenotype and downregulated Akt1/mTOR signaling. These results reveal that SMC-derived Fn-EDA potentiates phenotypic switching in human and mouse aortic SMCs and neointimal hyperplasia in the mouse. We suggest that targeting Fn-EDA could be explored as a potential therapeutic strategy to reduce neointimal hyperplasia.

翻译标题与摘要 下载文献
影响因子:4.65
发表时间:2020-01-01
DOI:10.1161/ATVBAHA.119.313602
作者列表:["Lee SY","Ahn JM","Mintz GS","Hong SJ","Ahn CM","Park DW","Kim JS","Kim BK","Ko YG","Choi D","Jang Y","Park SJ","Hong MK"]

METHODS:OBJECTIVE:The goal of this study was to determine the impact of late-acquired stent malapposition (LASM) on long-term clinical outcomes in patients treated with coronary stent implantation. Approach and Results: We investigated major adverse cardiac event during 10 years after 6-month intravascular ultrasound examination using our previous studies database. A total of 732 patients treated with bare-metal stent (54 LASM versus 678 non-LASM) and 529 patients treated with first-generation drug-eluting stent (82 LASM versus 447 non-LASM), who did not have clinical event or censoring at the time of follow-up intravascular ultrasound, were included for the present analysis. major adverse cardiac event was defined as the composite of cardiac death, target vessel-related myocardial infarction, target lesion revascularization and stent thrombosis. Multivariable adjustment and inverse probability weight were performed to consider baseline differences. After multivariable adjustment, LASM was related to a greater risk of major adverse cardiac event (hazard ratio, 1.666 [95% CI, 1.041-2.665]; P=0.0333) and very-late stent thrombosis (hazard ratio, 3.529 [95% CI, 1.153-10.798]; P=0.0271) than non-LASM in patients treated with first-generation drug-eluting stent, but not in those treated with bare-metal stent. Results were consistent after inverse probability weight. Among patients with LASM of first-generation drug-eluting stent, no late stent thrombosis occurred in patients who continued to receive dual antiplatelet therapy. CONCLUSIONS:The relationship between LASM and major adverse cardiac event might depend on the type of implanted stents during the long-term follow-up, highlighting the clinical significance of polymers and drugs in drug-eluting stent system.

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