New study IDs protein, molecular pathway as target for treating PH
PUM1 protein revealed as 'critical driver' of disease development
Altered activity of a protein called PUM1 plays a key role in the development of pulmonary hypertension (PH), according to a new study done in animal and cell models.
“Our study establishes PUM1 as a critical driver of PH pathogenesis [disease development],” the scientists wrote, adding that “this discovery is transformative for PH research.”
The findings indicate that this protein and the associated molecular pathway may be a key target for treating PH, the team noted.
The study, “The HIF1[alpha]-PUM1-KCNK3 axis drives pulmonary hypertension by destabilizing KCNK3 mRNA in pulmonary artery smooth muscle cells,” was published in the journal Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease.Â
PH refers to high pressure in the pulmonary arteries, which are the vessels that carry blood from the heart through the lungs. High pressure in these vessels puts strain on the heart, leading to a range of symptoms.
In this study, researchers focused specifically on group 3 PH, which refers to pulmonary hypertension associated with underlying lung disease or hypoxia, or low oxygen levels.
Previous research has shown that this type of PH is marked by dysregulation of pulmonary artery smooth muscle cell (PASMC) — the muscle cells that surround the pulmonary arteries, contracting to help squeeze blood through. Prior studies have indicated that PASMCs in people with PH have reduced levels of a protein called KCNK3, which normally helps regulate to regulate vascular tone, or the constriction/dilation of blood vessels. Essentially, low KCNK3 levels cause overgrowth and resistance to death in PASMCs, which contributes to high blood pressure.
Scientists say findings could lead to ‘novel strategy’ for PH treatment
However, while it’s been established that low KCNK3 levels in PASMCs contribute to group 3 PH, it’s been unclear what causes KCNK3 levels to be reduced in the first place. Now, a team of scientists in China has discovered a molecular pathway that may provide an explanation.
When oxygen levels are low, cells produce increased levels of HIF1alpha, which is a transcription factor — a protein that helps to control which genes are turned on or off within cells. The researchers showed that HIF1alpha is able to turn on the gene that encodes PUM1, which is an RNA-binding protein.
Messenger RNA, or mRNA, is an intermediary molecule that’s produced when genes are read to produce proteins. The researchers found that PUM1 is able to bind and destabilize mRNA from the gene encoding KCNK3, which ultimately leads the PASMCs to produce lower levels of KCNK3. When PASMCs have low KCNK3 levels, they take on features that drive disease.
“Our data strongly support the conclusion that dysregulation of the KCNK3 channel is a major mechanism through which PUM1 drives PASMC dysfunction,” the researchers wrote.
Putting these findings together gives a plausible molecular mechanism for how group 3 PH may develop. The theory is that low oxygen levels trigger increased amounts of HIF1alpha, which leads to increased levels of PUM1. That, in turn, reduces levels of KCNK3, ultimately leading to dysregulated activity of blood vessel muscle cells.
If this is true, then reducing PUM1 levels or otherwise interrupting this chain of molecular events could be a viable strategy for PH treatment, opening doors for future study.
“These findings not only reveal a previously unrecognized role of PUM1 in PH but also identify the HIF1[alpha]-PUM1-KCNK3 axis as a promising therapeutic target,” the researchers wrote. “Restoring KCNK3 expression by inhibiting PUM1-mediated RNA degradation may provide a novel strategy to counteract vascular remodeling in this lethal disorder.”
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