Uremic serum and solutes increase post-vascular interventional thrombotic risk through altered stability of smooth muscle cell tissue factor.
Uremic serum and solutes increase post-vascular interventional thrombotic risk through altered stability of smooth muscle cell tissue factor.
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DOI：
10.1161/circulationaha.112.118174
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发表时间：
2013-01-22
期刊：
影响因子：
37.8
通讯作者：
Edelman ER
中科院分区：
文献类型：
--
作者：
Chitalia VC;Shivanna S;Martorell J;Balcells M;Bosch I;Kolandaivelu K;Edelman ER
支架血栓形成（ST）是一种介入术后并发症，死亡率为50%，在高危患者中发病率急剧上升。慢性肾功能衰竭和终末期肾病已成为ST的特别强的危险因素，但其机制仍然难以捉摸。组织因子（TF）是损伤相关血栓形成的重要介质，并与ST有关。我们认为尿毒症调节局部血管壁中的TF，以诱导终末期肾病患者的介入后血栓形成。作为去内皮化的干预后状态的模型，我们将用尿毒症血清（从接受血液透析的ESRD患者中获得）预处理的原代人血管平滑肌细胞（vSMC）暴露于冠状动脉样血流。vSMC TF表达，活性，稳定性和翻译后修饰后，vSMC用尿毒症血清或溶质处理。我们发现尿毒症血清暴露后血凝块形成显著增加，而抗TF中和抗体治疗后血凝块形成显著减少。尿毒症血清诱导2- 3倍高TF表达和活性的vSMC独立的糖尿病。相关浓度的分离尿毒症溶质，如吲哚-3-乙酸（3.5 μg/mL）、硫酸吲哚酚（25 μg/mL）和尿酸（80 μg/mL），在细胞培养和流动环路模型中重现了这些效应。我们进一步表明，TF在基线时发生泛素化，尿毒症血清、吲哚-3-乙酸和硫酸吲哚酚通过抑制其泛素化显著延长TF半衰期。尿毒症环境是深刻的血栓形成和上调vSMC TF水平，通过增加TF稳定性和降低其泛素化。总之，这些数据首次证明，尿毒症TF的翻译后调节可能在尿毒症患者中观察到的ST风险增加中起致病作用。这些数据表明，减少vSMC TF的干预措施可能有助于预防ST，尿毒症溶质应被视为慢性肾功能衰竭患者ST的新风险因素。
Stent thrombosis (ST), a postinterventional complication with a mortality rate of 50%, has an incidence that rises precipitously in patients at risk. Chronic renal failure and end-stage renal disease have emerged as particularly strong ST risk factors, yet the mechanism remains elusive. Tissue factor (TF) is a crucial mediator of injury-related thrombosis and has been implicated for ST. We posit that uremia modulates TF in the local vessel wall to induce postinterventional thrombosis in patients with end-stage renal disease. As a model of the de-endothelialized, postinterventional state, we exposed primary human vascular smooth muscle cells (vSMCs) pretreated with uremic serum (obtained from ESRD patients on hemodialysis) to coronary-like blood flow. vSMC TF expression, activity, stability, and posttranslational modification were examined after vSMCs were treated with uremic serum or solutes. We found significantly greater clot formation after uremic serum exposure, which was substantially reduced with the prior treatment with anti-TF neutralizing antibody. Uremic sera induced 2- to 3-fold higher TF expression and activity in vSMCs independent of diabetes mellitus. Relevant concentrations of isolated uremic solutes such as indole-3-acetic acid (3.5 μg/mL), indoxyl sulfate (25 μg/mL), and uric acid (80 μg/mL) recapitulated these effects in cell culture and the flow loop model. We show further that TF undergoes ubiquitination at baseline and that uremic serum, indole-3-acetic acid, and indoxyl sulfate significantly prolong TF half-life by inhibiting its ubiquitination. The uremic milieu is profoundly thrombogenic and upregulates vSMC TF levels by increasing TF stability and decreasing its ubiquitination. Together, these data demonstrate for the first time that the posttranslational regulation of TF in uremia may have a causative role in the increased ST risk observed in uremic patients. These data suggest that interventions that reduce vSMC TF may help to prevent ST and that uremic solutes should be considered as novel risk factors for ST in patients with chronic renal failure.