A new study from the Center for Research on Redox Processes in Biomedicine (Redoxoma) has unveiled critical insights into how hyperglycemia, a common complication of diabetes, contributes to the increased risk of thrombosis. Published in the Journal of Thrombosis and Haemostasis, the findings could lead to new strategies for preventing cardiovascular complications in diabetic patients.
The study, which received support from the São Paulo Research Foundation (FAPESP), identifies the significant role of high blood sugar in triggering thrombosis, particularly through its impact on the inner lining of blood vessels. Ischemic events such as heart attacks and strokes, which are the leading causes of death in Brazil and other Latin American countries, are often driven by arterial thrombosis. Hyperglycemia, along with other factors like dyslipidemia and hypertension, contributes to cardiovascular disease, but its association with thrombosis is especially prominent.
Renato Simões Gaspar, the lead researcher, and Francisco Laurindo, professor at the University of São Paulo’s Medical School (FM-USP), explored how prolonged high blood sugar and diabetic ketoacidosis lead to endothelial dysfunction—an alteration in the blood vessel lining that promotes platelet adhesion and thrombus formation.
The study highlights the enzyme peri/epicellular protein disulfide isomerase A1 (pecPDI) as a crucial mediator in this process. PecPDI, located in both the endoplasmic reticulum and extracellular space, regulates platelet-endothelium interaction, triggering thrombosis under hyperglycemic conditions.
“We identified a specific molecular mechanism through which PDI influences thrombosis in diabetes,” Laurindo said. This discovery could inform future treatments aimed at mitigating thrombotic events in diabetics.
To understand the molecular interactions, the researchers developed a model using human umbilical vein endothelial cells grown in varying glucose concentrations to mimic both normal and high blood sugar conditions. Their findings revealed that platelets adhered significantly more to endothelial cells under hyperglycemic conditions. When pecPDI was inhibited, this effect was reversed, demonstrating that pecPDI plays a pivotal role in this process.
The team further explored the biophysical alterations in hyperglycemic cells, observing more organized actin filaments and increased hydrogen peroxide production—an oxidizing compound linked to cytoskeleton remodeling and platelet adhesion. Hyperglycemic cells were found to be stiffer, which enhances platelet adhesion, a key step in thrombosis.
Additionally, the researchers examined the secretome—the set of proteins secreted by cells—and discovered 947 proteins, eight of which were involved in cellular adhesion. By silencing three of these proteins, they pinpointed two—SLC3A2 and LAMC1—as essential for platelet binding. These proteins are involved in the extracellular matrix, a structure that helps cells stick to each other.
The study concludes that hyperglycemia promotes the secretion of adhesion-related proteins, and inhibiting pecPDI could prevent the secretion of these proteins, thus reducing the risk of thrombosis in diabetic patients. This research offers a promising direction for developing therapies aimed at preventing cardiovascular complications associated with diabetes.
Related topics:
Semaglutide Reduces Risk of Kidney Complications in Adults with Type 2 Diabetes
Essential Guidelines for Using Weight Loss Medications in Diabetes Management
Early-Onset Type 2 Diabetes Linked to Increased Mortality Risk
