UC San Diego researchers describe an imbalance of opposing cell signals that cause deadly disease, and how a novel monoclonal antibody therapy might treat or prevent it
Pulmonary arterial hypertension (PAH) is a type of high blood pressure in the lungs, in which blood vessels are narrowed, blocked, or destroyed, causing the heart to work harder and, in time, result in cardiac weakness and failure.
The disease is relatively rare, but affects an estimated 100,000 people in the United States, and results in 20,000 deaths annually. There is no cure.
Researchers at the University of California San Diego (UCSD) School of Medicine describe the underlying signaling pathway that results in PAH — and a novel monoclonal antibody therapy that blocks the disease’s abnormal blood vessel formation — in a study published on May 4th, 2022 in the journal Science Translational Medicine.
PAH advances at the cellular level by the growth of vascular smooth muscle cells (vSMC), which cause small arteries in the lungs to shrink, resulting in increasingly less oxygen in the circulation. Overexpression of the NOTCH ligand JAGGED-1, a binding protein involved in cell signaling and, in this case, the development of small pulmonary vSMCs, was the focus of a research team led by senior author Patricia A. Thistlethwaite, MD, Ph.D., professor of surgery at UC San Diego School of Medicine and cardiothoracic surgeon at UC San Diego Health.
They discovered that overexpression of the NOTCH3 ligand JAGGED-1 promotes vSMC proliferation, while DELTA-LIKE 4 inhibits it. The researchers subsequently created a therapeutic monoclonal antibody that selectively blocks JAGGED-1-induced NOTCH3 signaling, effectively curing pulmonary hypertension in two rodent models of the disease while producing no adverse side effects.
“These findings reveal two opposing roles of NOTCH ligands,” said Thistlethwaite. “Importantly, it opens the door to a potentially new, safe treatment for PAH, using a monoclonal antibody that selectively inhibits NOTCH3 activation in the lung vasculature.”
Reference: “JAGGED-NOTCH3 signaling in vascular remodeling in pulmonary arterial hypertension” by Yu Zhang, Moises Hernandez, Jonathan Gower, Nolan Winicki, Xena Morataya, Sebastian Alvarez, Jason X.-J. Yuan, John Shyy and Patricia A. Thistlethwaite, 4 May 2022, Science Translational Medicine.
Co-authors include: Yu Zhang, Moises Hernandez, Jonathan Gower, Nolan Winicki, Xena Morataya, Sebastian Alvarez, Jason X.-J. Yuan and John Shyy, all at UC San Diego.
Funding for this research came, in part, from the National Institutes of Health (grants R01HL119543 and R01HL132225).
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