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Targeting the molecular pathway that causes pulmonary hypertension – ScienceDaily

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Pulmonary arterial hypertension (PAH) is a type of high blood pressure in the lungs in which blood vessels constrict, clog, or break, causing the heart to work harder and eventually leading to heart failure and failure.

The disease is relatively rare, but it is estimated that about 100,000 people die in the United States and cause 20,000 deaths each year. There is no cure.

In a study published on May 4, 2022 Science Translational MedicineResearchers from the University of California, San Diego School of Medicine are describing a major signaling pathway that leads to PAH – and a new monoclonal antibody therapy that blocks abnormal blood vessel formation that characterizes the disease.

At the cellular level, PAH progresses with vascular smooth muscle cell proliferation (vSMC), leading to narrowing of small arteries in the lungs, resulting in progressively less oxygen in the blood. The research team, led by senior author Patricia A. Thistlethwaite, MD, professor of surgery at UC San Diego School of Medicine and UC San Diego Health cardiothoracic surgeon, focused on overexpression of the NOTCH ligand JAGGED-1, which binds cell signals and, in this case, in the development of small pulmonary vSMCs.

They found that overexpression of the NOTCH3 ligand, JAGGED-1, stimulates vSMC proliferation, but the DELCH-LIKE 4 NOTCH3 ligand inhibits it. The researchers then developed therapeutic monoclonal antibodies that selectively block JAGGED-1-induced NOTCH3 signaling, effectively reducing pulmonary hypertension in two models of rodent disease without toxic side effects.

“These findings show two opposing roles of NOTCH ligands,” Thistlethwaite said. “Importantly, this opens the door to a potentially new, safe treatment of PAH using monoclonal antibodies that selectively inhibit NOTCH3 activation in pulmonary vessels.”

Co-authors: Yu Zhang, Moses Hernandez, Jonathan Gower, Nolan Vinitsky, Xena Morataya, Sebastian Alvarez, Jason X.-J. Yuan and John Shai, all in UC San Diego.

Source of history:

Materials provided University of California – San Diego. The original was written by Scott La Phi. Note: Content can be edited by style and length.

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