PUBLICATION
PIEZO1 mediates a mechanothrombotic pathway in diabetes
- Authors
- Zhu, W., Guo, S., Homilius, M., Nsubuga, C., Wright, S.H., Quan, D., Kc, A., Eddy, S.S., Victorio, R.A., Beerens, M., Flaumenhaft, R., Deo, R.C., MacRae, C.A.
- ID
- ZDB-PUB-220303-3
- Date
- 2022
- Source
- Science Translational Medicine 14: eabk1707 (Journal)
- Registered Authors
- MacRae, Calum A.
- Keywords
- none
- MeSH Terms
-
- Animals
- Diabetes Mellitus, Type 2*
- Humans
- Hyperglycemia*/complications
- Ion Channels/metabolism
- Mechanotransduction, Cellular
- Thrombosis*
- Zebrafish/metabolism
- Zebrafish Proteins/metabolism
- PubMed
- 34985971 Full text @ Sci. Transl. Med.
Citation
Zhu, W., Guo, S., Homilius, M., Nsubuga, C., Wright, S.H., Quan, D., Kc, A., Eddy, S.S., Victorio, R.A., Beerens, M., Flaumenhaft, R., Deo, R.C., MacRae, C.A. (2022) PIEZO1 mediates a mechanothrombotic pathway in diabetes. Science Translational Medicine. 14:eabk1707.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping