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首页> 外文期刊>Life sciences >ATP-sensitive potassium channels expressed by human monocytes play a role in stasis-induced thrombogenesis via tissue factor pathway.
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ATP-sensitive potassium channels expressed by human monocytes play a role in stasis-induced thrombogenesis via tissue factor pathway.

机译：人单核细胞表达的ATP敏感性钾通道通过组织因子途径在血瘀诱导的血栓形成中起作用。

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Blood stasis is one of the key risk factors in deep vein thrombosis. Localized blood oxygen and glucose depletion are main characteristics observed during stasis. However, the causal chain leading to clot formation is still obscure. According to our hypothesis, energy depletion causes opening of K(ATP) channels present on monocytes, facilitating influx of calcium and triggering tissue factor-(TF)-dependent procoagulatory activity and eventually clot formation. Using Reverse-Transcript-PCR (RT-PCR) in magnetically enriched human monocytes, mRNA transcription of the K(ATP)-channel subunits Kir6.1 and Kir6.2 could be confirmed. Membrane potential and cytosolic calcium were recorded by time-resolved flow cytometry. The specific K(ATP)-channel opener pinacidil caused a glibenclamide-sensitive hyperpolarization of monocytes and a prolongation of cytosolic calcium transients triggered by purinergic stimulation. TF-initiated whole blood clotting time (TiFaCT) was accelerated comparing 2 and 8 h of simulated invitro blood stasis using blood of male healthy volunteers. Both with and without activation of the monocytes with 100 ng/ml LPS, the K(ATP)-channel blocker glibenclamide resulted in a significantly (p<0.001) prolonged clotting time after 8 h of stasis compared to vehicle control and LPS, respectively. In the course of stasis, flow cytometry showed an increase in monocytes expressing TF (0.1% and 1.3% after 2 and 8 h, respectively). LPS (100 ng/ml) increased the amount of TF expression significantly to 36%, whereas 30 microM glibenclamide partly reversed this increase down to 24%. Phosphatidylserine-exposure (PSE) on monocytes increased strongly during stasis by 11.2 times, a process which glibenclamide attenuated by 23%. LPS increased PSE further by 65%, which glibenclamide reduced by 50%. In conclusion, presence of integral subunits of K(ATP)-channels is demonstrated in human monocytes. These channels are able to enhance Ca(2+)-dependent intracellular signalling and can increase TF-activity and phosphatidylserine exposure thereby accelerating clot formation during stasis by monocytes.
机译：血瘀是深静脉血栓形成的关键危险因素之一。局部血氧和葡萄糖消耗是停滞期间观察到的主要特征。但是，导致凝块形成的因果链仍然不清楚。根据我们的假设，能量耗竭会导致单核细胞上存在的K（ATP）通道打开，促进钙的流入并触发组织因子-（TF）依赖的促凝活性，并最终形成血凝块。使用逆转录-PCR（RT-PCR）在富磁的人单核细胞中，可以确认K（ATP）通道亚基Kir6.1和Kir6.2的mRNA转录。通过时间分辨流式细胞仪记录膜电位和胞质钙。特定的K（ATP）通道开放剂吡那地尔引起嘌呤能刺激引起的格列本脲敏感的单核细胞超极化和胞浆钙瞬变的延长。使用男性健康志愿者的血液比较模拟体外血瘀的2小时和8小时，TF诱导的全血凝血时间（TiFaCT）加快。与赋形剂对照和LPS相比，在停滞8 h后，K（ATP）通道阻滞剂格列本脲在有和没有激活单核细胞的情况下均具有100 ng / ml LPS活化，从而显着延长了（p <0.001）凝血时间。在停滞过程中，流式细胞仪显示表达TF的单核细胞增加（分别在2 h和8 h后增加0.1％和1.3％）。 LPS（100 ng / ml）将TF表达量显着增加至36％，而30 microM格列本脲部分逆转了这一增加，降至24％。在停滞期间，单核细胞上的磷脂酰丝氨酸暴露（PSE）强烈增加了11.2倍，而格列苯脲减少了23％。 LPS使PSE进一步提高了65％，其中格列本脲降低了50％。总之，在人类单核细胞中证实了K（ATP）通道的完整亚基的存在。这些通道能够增强Ca（2+）依赖的细胞内信号传导，并可以增加TF活性和磷脂酰丝氨酸的暴露，从而加速单核细胞停滞期间的血块形成。

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