Effect of PAH Treatments Likely Goes Beyond Lowering Blood Presssure

Marisa Wexler MS avatar

by Marisa Wexler MS |

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In addition to lowering blood pressure, treatments for pulmonary arterial hypertension (PAH) probably work at least in part by preventing physical changes in the architecture of the lung’s blood vessels that are associated with the progression of the disease, according to a study.

“Our findings suggest that the beneficial aspects of current PAH-specific therapies are not only through the acute effects on vasoconstriction [narrowing of the arteries that leads to high blood pressure] but through their long-term effects on pulmonary vascular remodeling,” the researchers wrote.

The study, “β-Arrestin–Mediated Angiotensin II Type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension,” was published in the journal JACC: Basic to Translational Science.

PAH is characterized by abnormally high pressure in the lung’s blood vessels, which puts strain on the right side of the heart. A number of treatments for PAH have been approved; broadly, these medicines are thought to work mainly as vasodilators — that is, substances that prompt blood vessels to relax and widen, thus lowering blood pressure.

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Within the body, blood pressure (along with many other processes) is regulated by the action of signaling molecules, which bind to protein receptors on the surface of cells. The receptors then interact with proteins within the cell, which alters the activity of the cells and — as this happens across many cells in a tissue — change bodily functions.

One of the receptors that is important for regulating blood pressure is called angiotensin II type 1 receptor, or AT1R. A signaling molecule called angiotensin II binds to AT1R.

When that happens, it simultaneously activates two molecular signaling pathways within the cell: one that uses a type of protein called a G-protein, and another that uses a different protein type called beta-arrestin.

Scientists recently developed a “biased” activator, or agonist of AT1R called TRV023. When TRV023 binds to AT1R, it activates the beta-arrestin signaling, but it blocks the G-protein signaling.

Now, a team led by scientists at Duke University, in North Carolina, conducted a series of experiments in a rat model of PAH. The rats were treated either with TRV023, angiotensin II — which activates both AT1R pathways — or losartan. A medication that treats high blood pressure, Losartan is a compound that blocks both AT1R pathways.

Results showed that, whereas losartan improved survival in the PAH rats, TRV023 did not — even though it did have vasodilating properties. Losartan also led to improved hemodynamics, or measures of blood flow, after acute infusion, but not after chronic treatment over two weeks.

“These results demonstrate that antagonizing both [beta]-arrestin and G protein–dependent AT1R signaling is beneficial in PAH, but the selective inhibition of G protein–dependent signaling with a [beta]-arrestin–biased agonist (TRV023) did not improve hemodynamics or outcomes in PAH,” the researchers wrote.

“This suggests that [beta]-arrestin–mediated AT1R signaling contributes to PAH pathology [disease processes],” they wrote.

Further experiments showed that activating the beta-arrestin AT1R signaling with TRV023 led to increased proliferation (cell division) in blood vessel cells. This kind of increased division is believed to contribute to PAH by making the blood vessels thicker and stiffer.

Additional studies using cells taken from pulmonary hypertension patients also showed that TRV023 treatment promoted this proliferation.

“We demonstrated that an AT1R [beta]-arrestin–biased agonist that acts as a vasodilator (by blocking G protein–mediated signaling) while promoting signaling through [beta]-arrestins did not have a beneficial effect and led to adverse pulmonary vascular remodeling and worse outcomes,” the researchers wrote.

These results suggest that current PAH treatments work not only through vasodilation, or the widening of blood vessels — shown to enhance blood flow and reduce blood pressure — but also through their long-term impact on pulmonary vascular remodeling, or changes in the architecture of the lung’s blood vessels, according to the researchers.

“Indeed, it is likely that the beneficial effects of current PAH therapies act both as vasodilators and anti-proliferative agents,” the team wrote.

A noted limitation of this study is that the researchers were unable to test a molecule that activates AT1R G-protein signaling and blocks beta-arrestin signaling, because no such molecule has yet been identified. The team also noted a need for further studies on other signaling pathways that regulate blood pressure and are targeted by available PAH treatments.