PIEZO1 mediates a mechanothrombotic pathway in diabetes
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PIEZO1 mediates a mechanothrombotic pathway in diabetes. / Zhu, Wandi; Guo, Shihui; Homilius, Max; Nsubuga, Cissy; Wright, Shane H; Quan, Dajun; Kc, Ashmita; Eddy, Samuel S; Victorio, Rachelle A; Beerens, Manu; Flaumenhaft, Robert; Deo, Rahul C; MacRae, Calum A.
In: SCI TRANSL MED, Vol. 14, No. 626, eabk1707, 05.01.2022.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - PIEZO1 mediates a mechanothrombotic pathway in diabetes
AU - Zhu, Wandi
AU - Guo, Shihui
AU - Homilius, Max
AU - Nsubuga, Cissy
AU - Wright, Shane H
AU - Quan, Dajun
AU - Kc, Ashmita
AU - Eddy, Samuel S
AU - Victorio, Rachelle A
AU - Beerens, Manu
AU - Flaumenhaft, Robert
AU - Deo, Rahul C
AU - MacRae, Calum A
PY - 2022/1/5
Y1 - 2022/1/5
N2 - 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 activated PIEZO1 transcription 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.
AB - 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 activated PIEZO1 transcription 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.
U2 - 10.1126/scitranslmed.abk1707
DO - 10.1126/scitranslmed.abk1707
M3 - SCORING: Journal article
C2 - 34985971
VL - 14
JO - SCI TRANSL MED
JF - SCI TRANSL MED
SN - 1946-6234
IS - 626
M1 - eabk1707
ER -
