Researchers from Indiana University and the University of Notre Dame focused on reversing vascular remodeling through an epigenetic pathway involving the protein SPHK2, as reported in the journal Circulation Research. A potential treatment has been discovered. This innovative approach could transform the treatment of this serious lung disease.
Researchers at Indiana University School of Medicine’s South Bend Regional Campus and colleagues at the University of Notre Dame have discovered a new therapeutic target to treat pulmonary hypertension. This form of hypertension particularly affects blood vessels in the lungs. The team’s research and findings were recently published in the journal circulation research.
Pulmonary hypertension is a complex and often fatal condition in which the heart works harder than normal to pump blood to the lungs. The exact cause of pulmonary hypertension is unknown, but one of its hallmarks is thickening of pulmonary blood vessels caused by cell overgrowth, also known as vascular remodeling.
Discovery of new treatments
Margaret A. Schwartz, M.D., professor of pediatrics at IU School of Medicine and senior author of the study, said there are few treatments for pulmonary hypertension, and they usually treat the symptoms of vascular remodeling rather than the remodeling itself. Ta.
Dr. Schwartz said that an interesting finding of her team was the discovery of an epigenetic pathway through the protein SPHK2 that can reduce and potentially reverse vascular remodeling in pulmonary hypertension.
Dr. Dushani Ranasinghe (left) and Margaret Schwartz, MD, attend the University of Notre Dame Ranasinghe graduation ceremony.Credit: Provided by Margaret Schwartz
“This is one of the first reversible mechanisms of pulmonary hypertension identified,” she says. “Patients with pulmonary hypertension are usually given drugs to lower blood vessel pressure in the lungs or to help the heart contract to pump blood, both of which are symptoms of vascular remodeling. Our research focuses on targeting an epigenetic reversal of this mechanism. Ultimately, stopping the vascular remodeling process entirely may be the answer.”
Schwartz said the concept is similar to cancer treatment.
“In the case of cancer, we don’t just treat the symptoms, we stop the tumor from growing,” she says. “Vascular remodeling is a different mechanism, but the idea is that treatments target the mechanism rather than the symptoms.”
Main findings and future directions
Other key findings from the study include:
- SPHK2 promotes the development of pulmonary hypertension through hyperacetylation of histone H3K9 and contributes to vascular remodeling in pulmonary artery smooth muscle cells (PASMCs).
- SPHK2 deficiency results in decreased pulmonary vascular resistance, right ventricular hypertension, and thickened distal vessel walls.
- EMAP (endothelial monocyte activation polypeptide) II plays an important role in stimulating the nuclear SPHK2/S1P epigenetic regulatory axis, suggesting cooperation between SPHK2 and S1P.
- EMAPII may be a major driving force of epigenetic-mediated vascular PASMC reprogramming and remodeling in pulmonary hypertension.
- Pulmonary endothelial cells are priming factors for the EMAPII/SPHK2/S1P axis that alters PASMC-specific acetylome through histone H3K9 hyperacetylation.
Schwartz and the study’s lead author, Dr. Dushani Ranasinghe, who was a member of Schwartz’s lab when Schwartz was a graduate student at Notre Dame, also thanked Dr. Schwartz for this episode. were interviewed about their findings. Podcast “Discover CircRes”It is produced by. circulation research.
Dr. Schwartz said the next steps in her research include collaborating with Brian Bragg, director of the Warren Center for Drug Discovery and Development at the University of Notre Dame, to further explore the SPHK2 protein as a therapeutic target for pulmonary hypertension. Stated.
Reference: “Changes in smooth muscle cell histone acetylome through the SPHK2/S1P axis promote pulmonary hypertension” A. Dushani CU Ranasinghe, Maggie Holohan, Kalyn M. Borger, Deborah L. Donahue, Rafael D. Kuc, Martin Gerig, Andrew Kim, Victoria A. Propris, Frances J. Castelino, Margaret A. Schwartz, September 12, 2023. circulation research.
DOI: 10.1161/CIRCRESAHA.123.322740
Other IU authors on the study include Maggie Holohan and Martin Gerrig.
This research was made possible in part through funding from the following institutions: National Institutes of HealthLilly Endowment, O’Brien Family Excellence Fund, National Science Foundation, Buckner Family Scholarship.
Source: scitechdaily.com
