PIEZO1 mediates a mechanothrombotic pathway in diabetes.
PIEZO1 mediates a mechanothrombotic pathway in diabetes.
复制标题
PIEZO1 介导糖尿病中的机械血栓形成途径。
DOI：
10.1126/scitranslmed.abk1707
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发表时间：
2022
影响因子：
17.1
通讯作者：
MacRae,CalumA
中科院分区：
文献类型：
--
作者：
Zhu,Wandi;Guo,Shihui;Homilius,Max;Nsubuga,Cissy;Wright,ShaneH;Quan,Dajun;Kc,Ashmita;Eddy,SamuelS;Victorio,RachelleA;Beerens,Manu;Flaumenhaft,Robert;Deo,RahulC;MacRae,CalumA
血栓形成是糖尿病、冠心病和感染等人类常见疾病的主要并发症，仍然是全球健康负担。目前针对一般凝血级联的抗凝疗法与不可预测的不良出血效应相关，因为对止血的了解仍然不完整。在这里，通过对患者外周血样本的潜在表型进行微扰筛查，我们发现了 2 型糖尿病 (T2DM) 患者多个血统中主要机械感觉离子通道 Piezo1 的失调。高血糖激活成熟血细胞中的 PIEZO1 转录并选择高表达 Piezo1 的造血干细胞克隆。 T2DM 患者血小板、红细胞和中性粒细胞中 Piezo1 活性升高引发离散的促血栓细胞反应。在人类血液和斑马鱼遗传模型中，抑制 Piezo1 可以防止血栓形成，特别是在高血糖情况下。我们的研究结果确定了精确调节 T2DM 机械诱导血栓形成的候选靶标，以及预测患者特定风险的潜在筛查方法。造血过程中细胞谱系的持续重塑是 T2DM 血栓风险的一个组成部分，相关机制可能在慢性疾病中发挥更广泛的作用。
Thrombosis is the leading complication of common human disorders including diabetes, coronary heart disease, and infection and remains a global health burden. Current anticoagulant therapies that target the general clotting cascade are associated with unpredictable adverse bleeding effects, because understanding of hemostasis remains incomplete. Here, using perturbational screening of patient peripheral blood samples for latent phenotypes, we identified dysregulation of the major mechanosensory ion channel Piezo1 in multiple blood lineages in patients with type 2 diabetes mellitus (T2DM). Hyperglycemia activatedPIEZO1transcription in mature blood cells and selected high Piezo1–expressing hematopoietic stem cell clones. Elevated Piezo1 activity in platelets, red blood cells, and neutrophils in T2DM triggered discrete prothrombotic cellular responses. Inhibition of Piezo1 protected against thrombosis both in human blood and in zebrafish genetic models, particularly in hyperglycemia. Our findings identify a candidate target to precisely modulate mechanically induced thrombosis in T2DM and a potential screening method to predict patient-specific risk. Ongoing remodeling of cell lineages in hematopoiesis is an integral component of thrombotic risk in T2DM, and related mechanisms may have a broader role in chronic disease.