About 80% of individuals with type 2 diabetes mellitus (T2DM) die from thrombotic complications. An ion channel protein known as Piezo1 is known to facilitate thrombus formation, and now researchers at Brigham and Women’s Hospital have shown it may represent a new target for therapies to prevent thrombosis in patients with T2DM who are at high risk.
Calum A. MacRae, MD, PhD, vice chair for scientific innovation in the Department of Medicine at Brigham and Women’s Hospital, Wandi Zhu, PhD, a research fellow in medicine, and colleagues explain the details in Science Translational Medicine.
This study was part of a larger effort to identify latent blood markers of various chronic diseases. To facilitate their work, the researchers created a novel method for automated screening of whole-blood samples (in this study, they compared samples from patients with and without T2DM).
The team also assessed the effect of hyperglycemia on Piezo1 expression ex vivo and in vivo, both in mature blood and during hematopoiesis, and investigated the effects of gain-of-function Piezo1 expression and, conversely, Piezo1 inhibition.
Important observations about the regulation of Piezo1 in T2DM were:
- Piezo1 expression and functional responses were upregulated in multiple peripheral blood cell types—both mature cells and hematopoietic stem cells (HSCs)—from patients with T2DM compared to those from controls
- Upregulation depended on higher glucose levels in white blood cells and extracellularly
- In vivo experiments in zebrafish showed that high piezo1–expressing HSCs had advantages in proliferation and differentiation, and possibly survival, over low piezo1–expressing HSCs—and those advantages were further modulated by hyperglycemia
- Piezo1 triggered prothrombotic responses in human platelets, red blood cells and neutrophils
Important results of gain-of-function experiments and Piezo1 inhibition were:
- Transgenic zebrafish that overexpressed a human Piezo1 variant exhibited shorter time to vessel occlusion in response to induced vascular injury, compared with wild-type fish; the opposite was observed in piezo1-null fish
- Low piezo1 in zebrafish reduced susceptibility to thrombosis in hyperglycemic conditions without resulting in excess bleeding
Outlook for Clinical Translation
This study suggests it will be possible to target Piezo1 locally in blood—isolate thrombotic pathways from normal hemostatic processes. If so, improved antithrombotic therapies could be developed that are associated with less risk of bleeding.
Compounds that reduce Piezo1 function are beginning to be identified, and the ex vivo and in vivo assays the researchers developed will be a useful way to screen drug candidates. The assays will also be a tool for assessing individual patients’ Piezo1 function, and thus their risk of thrombosis, in T2DM and perhaps other chronic diseases.