A new study in mice has identified FXR1, a protein in the same family as the protein involved in Fragile X syndrome, as a potential target for creating a new type of blood pressure-lowering drug, according to preliminary research presented at the American Heart Association’s Vascular Discovery: From Genes to Medicine 2022 Scientific Sessions. Held May 12-14, 2022 in Seattle, the meeting is a global exchange of the latest advances in new and emerging scientific research in the fields of arteriosclerosis, thrombosis, vascular biology, peripheral vascular disease, vascular surgery and functional genomics.
Fragile X syndrome, or FXS, is the most common known cause of hereditary intellectual disability caused by mutations on the X chromosome. The CDC estimates that FXS affects 1 in 7,000 men and 1 in 11,000 women born in the US each year. FXS can lead to developmental delays, learning disabilities and behavioral problems, with symptoms being more severe in boys than girls.
FXS is caused by mutations in the FMR1 gene, which codes for an RNA-binding protein FMRP that is believed to play a role in the development of connections between nerve cells in the brain.
FXR1 belongs to the same family of RNA-binding proteins as FMRP and is muscle specific. RNA-binding proteins help turn genes on and off and are essential for many cellular processes.
“In my previous research on FXR1, I expected more transcription factors, translation factors, factors that regulate mRNA to interact with FXR1,” said Amanda St. Paul, the study’s lead author and a Ph.D. candidate at the Lewis Katz School of Medicine at Temple University in Philadelphia. “It was really surprising to find that FXR1 binds to many actin-binding proteins and other proteins involved in the cytoskeleton.” Transcription and translation factors are proteins that help turn certain genes on and off. Actin proteins are responsible for the contraction and relaxation of muscles.
St. Paul and colleagues developed a mouse model in which FXR1 can be removed in smooth muscle cells — the same kind that make up blood vessels in humans. The mice were genetically modified so that the FXR1 gene could be removed by administering the drug tamoxifen.
With the FXR1 gene deleted, the researchers noted that the vascular smooth muscle cells behaved differently compared to those of the mice with active FXR1.
“We found that vascular smooth muscle cells without FXR1 don’t proliferate, they don’t attach, they don’t migrate, which are activities that depend on a properly functioning cytoskeleton. And this is all a vascular smooth muscle cell should do,” said Saint Paul .
Turning off FXR1 had another eye-opening effect: “If you took FXR1 away from smooth muscle in these mice, they also had a lower diastolic blood pressure compared to control mice,” St. Paul said.
The analysis showed that:
- Depleting FXR1 reduced the ability of blood vessel cells to contract; and
- When FXR1 is removed, the mice had reduced diastolic blood pressure compared to control mice. This was measured using telemetry, an in vivo blood pressure measurement.
According to St. Paul, these findings suggest that targeting FXR1 in vascular smooth muscle cells, or the contractile pathway it regulates, may hold a promising avenue for antihypertensive drug development. “Many drug targets don’t target the cytoskeleton. Because FXR1 is muscle-specific, it gives us a specific target and pathway to explore further,” she said. “Millions of people have high blood pressure; it’s important to find new ways to improve blood pressure.”
Future work for St. Paul and colleagues includes investigating whether the activity of FXR1 in smooth muscle cells is dependent on its ability to interact with cytoskeletal proteins and whether removing FXR1 is effective in lowering blood pressure in a hypertensive mouse model.
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American Heart Association Vascular Discovery: From Genes to Medicine 2022 Science Sessions
Provided by American Heart Association
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