Targeting beta arrestin 1 protein could offer new hope for PH treatment: Study
When it's missing, pathway that helps widen pulmonary arteries is impaired
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A lack of the protein beta-arrestin 1 reduces the ability of pulmonary arteries to widen, leading to pulmonary hypertension (PH), according to a new study in mice.
The study found that when beta-arrestin 1 is missing, the signaling pathway that drives the widening of pulmonary arteries, the blood vessels responsible for transporting blood through the lungs, is impaired. As a result, blood pressure in the pulmonary arteries increases.
“In the future, we might be able to develop an activator for beta-arrestin 1 potentially leading to more effective treatments for pulmonary hypertension,” Bernd Fleischmann, PhD, professor at the University of Bonn in Germany and co-author of the study, said in a university news story.
The researchers described their findings in “Beta arrestin 1 is a key regulator of pulmonary vascular tone,” published in PNAS.
Do beta-arrestins regulate blood vessel diameter?
PH is characterized by high blood pressure in the pulmonary arteries, driven by excessive growth of endothelial cells lining blood vessel walls and of smooth muscle cells.
Normally, the regulation of blood vessel diameter involves the release of nitric oxide (NO). This signaling molecule activates the enzyme soluble guanylate cyclase (sGC), which is present in smooth muscle cells. Importantly, sGC produces cGMP, a chemical that relaxes blood vessels, thus reducing blood pressure.
In this study, researchers in Germany investigated whether beta-arrestins, proteins that regulate smooth muscle tone in the airways, also regulate blood vessel diameter.
“At first glance, the beta arrestin protein has nothing to do with these processes,” said Daniela Wenzel, MD, professor at Ruhr University Bochum and the study’s senior author. “But beta arrestin can do much more. It is also a scaffold protein that connects to other signaling molecules and helps guide them to where they need to be in the cell.”
The team conducted experiments in genetically modified mice lacking a specific beta-arrestin subtype: beta-arrestin 1 or beta-arrestin 2. They found that the pulmonary arteries of mice lacking beta-arrestin 1 had impaired NO-dependent dilation, due to low sGC activity.
These findings highlight the important role of [beta-arrestin 1] in regulating pulmonary vascular tone and propose it as a potential therapeutic target for the treatment of PH.
This meant that upon NO administration, these blood vessels did not widen to the same extent as in normal mice or mice lacking beta-arrestin 2.
“It is clear that beta arrestin 1 is involved in the development of pulmonary hypertension,” added Alexander Seidinger, PhD, researcher at Ruhr University Bochum and one of the study’s first authors. “And, of course, we wanted to know the underlying mechanism.”
Further experiments demonstrated that beta-arrestin 1 binds sGC and helps sensitize the enzyme to NO by transporting an enzyme that makes a required chemical modification.
In addition, the team found that mice without beta-arrestin 1, either in all cells or specifically in smooth muscle cells, developed PH.
“These findings highlight the important role of [beta-arrestin 1] in regulating pulmonary vascular tone and propose it as a potential therapeutic target for the treatment of PH,” the researchers wrote.
Fleischmann added that “this discovery opens up a lot of questions. In the future, we might be able to develop an activator for beta arrestin 1 potentially leading to more effective treatments for pulmonary hypertension.”
