Vásquez’s research highlights importance of pressure-sensing protein in sickle cell disease
Recent research from the lab of Valeria Vásquez, PhD, associate professor in the Department of Biochemistry and Molecular Biology at McGovern Medical School, shows that PIEZO1, an ion channel that helps regulate red blood cell volume, may be a key driver of cell dehydration, hemolysis, and inflammation in sickle cell disease.
The paper, titled “Enhanced PIEZO1 Function Contributes to the Pathogenesis of Sickle Cell Disease,” was published in the Proceedings of the National Academy of Sciences of the United States of America.
“Our publication reveals that a pressure-sensing protein in red blood cells, known as PIEZO1, is more active in individuals with sickle cell disease, as well as in murine models of the disease,” Vásquez said.
Sickle cell occurs when a genetic change in hemoglobin causes red blood cells to become rigid, dehydrated, and prone to breaking apart. Because PIEZO1 helps regulate cell volume by controlling the movement of charged particles, Vásquez set out to determine whether its function is altered in sickle cells and whether correcting abnormalities could improve cell function.
“We initiated this project by building on our prior work showing that dietary fatty acids modulate PIEZO1, and on emerging evidence that PIEZO1 plays a central role in red blood cell physiology,” Vásquez said.
Her team partnered with Kenneth Ataga, MD, and Laila Elsherif, MS, PhD, at the Center for Sickle Cell Disease at the University of Tennessee Health Science Center to obtain patient samples for electrophysiological recordings. After using these recordings to determine that PIEZO1 was overactive in red blood cells from patients with sickle cell disease, the team used a murine model of the disease — the Townes model from The Jackson Laboratory.
The researchers then gave the murine models a diet enriched in eicosapentaenoic acid, which is commonly found in fish oil. This diet brought PIEZO1 levels back to normal in their red cells and led to healthier lab readouts with lower hemolysis, improved lipid and glucose profiles, and drops in several inflammatory cytokines. The diet also cut the fraction of cells that sickled during low-oxygen challenges, suggesting that targeting PIEZO1 could help restore red-cell hydration and reduce hemolysis and inflammation in patients.
“These experiments corroborated our findings, and in the murine model, we fed an eicosapentaenoic acid-enriched diet that reduced PIEZO1 overactivity and ameliorated symptoms associated with sickle cell disease,” Vásquez said. “Going forward, we would like to prioritize clinical translation by launching trials with eicosapentaenoic acid, and evaluating emerging PIEZO1 inhibitors as they become available as add-on therapies for sickle cell disease.”