Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation.
Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Republic of Tatarstan, Russian Federation; Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
J Thromb Haemost. 2023 Sep;21(9):2418-2429. doi: 10.1016/j.jtha.2023.05.022. Epub 2023 Jun 1.
Piezo1 is a mechanosensitive cationic channel that boosts intracellular [Ca]. Compression of red blood cells (RBCs) during platelet-driven contraction of blood clots may cause the activation of Piezo1.
To establish relationships between Piezo1 activity and blood clot contraction.
Effects of a Piezo1 agonist, Yoda1, and antagonist, GsMTx-4, on clot contraction in vitro were studied in human blood containing physiological [Ca]. Clot contraction was induced by exogenous thrombin. Activation of Piezo1 was assessed by Ca influx in RBCs and with other functional and morphologic features.
Piezo1 channels in compressed RBCs are activated naturally during blood clot contraction and induce an upsurge in the intracellular [Ca], followed by phosphatidylserine exposure. Adding the Piezo1 agonist Yoda1 to whole blood increased the extent of clot contraction due to Ca-dependent volumetric shrinkage of RBCs and increased platelet contractility due to their hyperactivation by the enhanced generation of endogenous thrombin on activated RBCs. Addition of rivaroxaban, the inhibitor of thrombin formation, or elimination of Ca from the extracellular space abrogated the stimulating effect of Yoda1 on clot contraction. The Piezo1 antagonist, GsMTx-4, caused a decrease in the extent of clot contraction relative to the control both in whole blood and in platelet-rich plasma. Activated Piezo1 in compressed and deformed RBCs amplified the platelet contractility as a positive feedback mechanism during clot contraction.
The results obtained demonstrate that the Piezo1 channel expressed on RBCs comprises a mechanochemical modulator of blood clotting that may be considered a potential therapeutic target to correct hemostatic disorders.
Piezo1 是一种机械敏感性阳离子通道，可增加细胞内的 [Ca]。血小板驱动的血栓收缩过程中对红细胞（RBC）的压缩可能导致 Piezo1 的激活。
建立 Piezo1 活性与血栓收缩之间的关系。
在含有生理 [Ca]的人血液中研究了 Piezo1 激动剂 Yoda1 和拮抗剂 GsMTx-4 对体外血栓收缩的影响。通过外源性凝血酶诱导血栓收缩。通过 RBC 中的 Ca 内流和其他功能和形态特征评估 Piezo1 的激活。
在血栓收缩过程中，天然激活了受压 RBC 中的 Piezo1 通道，并引起细胞内 [Ca]的激增，随后暴露出磷脂酰丝氨酸。向全血中添加 Piezo1 激动剂 Yoda1 会由于 RBC 因 Ca 依赖性体积收缩而导致血栓收缩程度增加，并由于在激活的 RBC 上增强的内源性凝血酶的产生导致血小板收缩力增强而增加，从而增加血小板收缩力。添加凝血酶形成抑制剂 rivaroxaban 或从细胞外空间去除 Ca 会消除 Yoda1 对血栓收缩的刺激作用。Piezo1 拮抗剂 GsMTx-4 相对于对照在全血和富含血小板的血浆中均导致血栓收缩程度降低。在血栓收缩过程中，受压和变形的 RBC 中激活的 Piezo1 作为正反馈机制放大了血小板的收缩力。
研究结果表明，RBC 上表达的 Piezo1 通道是血栓形成的机械化学调节剂，可被认为是纠正止血障碍的潜在治疗靶标。
