Key gene, protein changes seen in people with PoPH in new study
Findings provide framework for understanding role played by liver
Scientists have identified gene, protein, and signaling pathway alterations in the livers of people with portopulmonary hypertension (PoPH) — a form of pulmonary arterial hypertension (PAH) usually associated with liver disease — that could reflect underlying mechanisms of the rare disorder.
Compared with liver disease patients without PoPH, those with this form of PAH showed changes in inflammatory signaling, growth factors, and estrogen signaling. Data showed these patients also exhibited signs of alterations near the blood vessels traveling from the liver to the heart, called the peri-central region.
“Our findings provide a framework for understanding how the liver peri-central region might influence liver-lung crosstalk” — simply put, organ-to-organ communication between the liver and lungs — “and promote PoPH pathogenesis” or disease development, the researchers wrote.
As such, this study “may ultimately lead to new targets and strategies for clinical trials,” the team wrote.
Seeking to better understand the mechanisms of PoPH
PAH is characterized by a narrowing of the vessels, called the pulmonary arteries, that supply blood from the heart to the lungs.
In a type of PAH known as portopulmonary hypertension, or PoPH, this also is accompanied by high pressure in the portal vein, which is responsible for directing blood from the gastrointestinal tract to the liver. This high pressure typically occurs as a consequence of severe liver disease.
The mechanisms that underlie PoPH, and how dysfunction in the liver could lead to vascular remodeling — structural changes thought to underlie blood vessel narrowing — in the lungs are not fully understood.
To learn more, a team of U.S. scientists performed a technique called RNA sequencing to compare gene activity in the livers of people with cirrhosis, a severe liver disease, to those of individuals with or without PoPH.
Liver samples were obtained from nine patients at the time of a liver transplant. Among the patients were five with cirrhosis caused by alcoholism but without PoPH, and four with PoPH.
A number of characteristics unique to PoPH were observed among the liver disease patients, including an altered inflammatory profile.
Moreover, changes in the activity of three genes of interest — BMPR2, ESR1, and FLT1 — were noted by the researchers.
BMPR2, which encodes production of the bone morphogenic protein receptor 2, was found at lower levels in liver cells from PoPH patients. Mutations in BMPR2 are a leading genetic cause of heritable PAH, and low gene activity is seen in non-heritable forms of the disease.
Meanwhile, ESR1, which encodes production of a receptor protein that mediates the effects of estrogen in the body, had increased activity, which also has been previously linked to PAH.
FLT1, a member of another growth factor signaling pathway, similarly had increased activity.
Consistently, levels of the BMPR2, ESR1, and FLT1 proteins were altered in the liver tissue of PoPH patients, but the changes were found to be most pronounced in cells surrounding the central hepatic vein, which transports blood from the liver toward the heart.
As such, the scientists looked for other changes in this peri-central area. They observed alterations in pathways associated with arginine synthesis as well as an enrichment of the growth differentiation factor 15 (GDF15) pathways, both of which have been linked to PAH.
Future research may help ID new treatment targets in PoPH
Another BMP protein called BMP9 previously had been found to be at lower circulating levels in PoPH patients.
While BMP9 gene activity was not found to be altered in this study, circulating levels of the protein were diminished in PoPH patients and could distinguish them from other liver disease patients and people with idiopathic PAH, or PAH without a known cause.
The researchers noted that the genes, protein, and pathways identified in this study “have all been implicated previously in PAH and PoPH pathogenesis.”
Overall, the researchers believe that imbalances in these various pathways might disrupt the control of cell growth in the pulmonary arteries, leading to excessive cell growth and vascular remodeling that narrows the vessels.
Altered inflammation, which also was observed, likely contributes as well, the team noted.
“Further confirmation of the importance of these proteins and pathways to PoPH disease pathogenesis is clearly warranted,” the scientists wrote.
The team noted that the central hepatic vein, where many of these changes were observed, is “the closest avenue of communication between the hepatic and pulmonary circulation.”
This could help explain how changes in the liver ultimately affect pulmonary circulation. Future research should aim to further clarify this role, “potentially identifying targetable mediators capable of disrupting this pathogenic process and ameliorating PoPH disease,” the scientists wrote.
The researchers also noted that to fully study this relationship, it would be ideal to look at gene activity in both liver and lung tissue simultaneously, but said that is a “vanishingly rare clinical opportunity.”