Activating BMPR2 Protein Supported as PAH Treatment Strategy

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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BMPR2 | Pulmonary Hypertension News | illustration of mice with test tubes in lab

Newly revealed biological mechanisms that underlie the development of pulmonary arterial hypertension (PAH) support activating BMPR2, the protein mutated in most familial PAH cases, as a treatment strategy, according to a study that investigated human cells and mouse models.

A recent case series showed potential for the BMPR2-activator FK506 (tacrolimus, approved for organ transplant and atopic dermatitis) as a treatment for end-stage PAH, which resulted in stabilized heart function and fewer hospitalizations.

Also, a complete Phase 2 clinical trial (NCT01647945) evaluated FK506’s impact in a small PAH patient group. The study demonstrated that although some patients responded with BMPR2 increases and walked farther in the six-minute distance test, the changes observed were not statistically significantly. Regardless, the study’s sponsor noted the data supported a Phase 2b efficacy trial.

The study, “Suppression of BMP signaling by PHD2 deficiency in Pulmonary Arterial Hypertension,” was published in Pulmonary Circulation.

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PAH is characterized by the narrowing of the small blood vessels, called pulmonary arteries, that transport blood through the lungs.. As a result, blood pressure rises, making it harder for the heart to pump blood.

This narrowing is caused by vascular remodeling, an abnormal thickening of the blood vessels’ walls. The underlying molecular mechanisms of this process remain poorly understood, however.

About 80% of familial PAH cases are caused by mutations in BMPR2, a protein that regulates the growth of blood vessel cells in the lungs. These mutations have been linked to the overgrowth of smooth muscle cells in pulmonary arteries, causing them to narrow. Further, BMPR2 is reduced in the lungs in about 20% of sporadic cases, but the biological reason for this is not known.

Scientists at the University of Arizona developed the first pulmonary hypertension mouse model by disrupting the Egln1 gene, which provides instructions for the PHD2 enzyme.

PHD2 interacts with another protein called HIF-2 alpha, which is part of a larger HIF protein complex that stimulates blood vessel growth and plays a critical role in the body’s ability to adapt to changing oxygen levels.

When enough oxygen is available, the PHD2 enzyme is active and stimulates the breakdown of HIF-2 alpha, suppressing blood vessel growth. Under low oxygen conditions (hypoxic), PHD2 is less active, leaving more HIF-2 alpha (and HIF) to trigger forming new blood vessels and red blood cells to maximize the amount of oxygen that can be delivered to the body. Studies indicate PHD2 is involved in the body’s adaptation to high altitudes.

Disrupting the Egln1 gene leads to a lack of PHD2. As a result, HIF is highly active and causes the excess formation of blood vessels, giving rise to vascular remodeling and blockages, and right heart failure, mimicking many of the clinical features of PAH.

Using this mouse model, the team investigated the relationship between PHD2, HIF, and BMPR2 to better understand PAH development’s molecular mechanisms.

In the lungs of these mice, BMPR2 protein was reduced, and several genes controlled by BMPR2 were less active. Conversely, the Grem1 gene, and its encoded protein (GREM1) that suppresses BMPR2 signaling, were markedly increased.

“These data demonstrate the suppression of BMP signaling in the lung ECs [endothelial cells, which line blood vessels] of Egln1-deficient mice,” the researchers wrote.

Deleting the gene that encodes for the HIF-2 alpha protein in these Egln1-deficient mice completely blocked pulmonary hypertension development and resulted in BMPR2 signaling normalizing.

PHD2 production was then suppressed in human endothelial cells to support translating these findings to PAH patients. Suppressing PHD2 reduced BMPR2 protein and related signaling, as shown by a decrease in the activity of genes controlled by BMPR2 and an increase in genes that block BMPR2 production, including GREM1.

In cells where both PHD2 and HIF-2 alpha were suppressed, increases in GREM1 were suppressed, “suggesting that GREM1 [production] was controlled by [HIF-2 alpha],” the researchers wrote.

While further experiments confirmed that HIF-2-alpha directly controlled GREM1 production, the data didn’t support the direct regulation of HIF-2-alpha on BMPR2 production.

“Further studies are warranted to address the mechanisms that how HIF regulates BMPR2 and other BMP signaling components,” the researchers said.

Lastly, because BMPR2 signaling plays an essential role in PAH development, the researchers treated PAH mice with a potent BMPR2 activator called FK506, also known as tacrolimus. FK506 treatment significantly decreased blood pressure in the pulmonary artery and halted the enlargement in the heart’s right ventricle of PAH mice.

“Taken together, activation of BMP signaling represents a promising approach for the treatment of PAH patients,” the scientists wrote.

A Conversation With Rare Disease Advocates