- The results of a new study in mice could help develop new drugs to treat high blood pressure.
- The researchers studied mice without a protein called FXR1, which is linked to the protein involved in fragile X syndrome; mice without FXR1 had lower diastolic blood pressure than mice with the protein.
- The results suggest two mechanisms by which FXR1 may regulate blood pressure and vascular contractility: mRNA stability and functional activity through protein-protein interactions.
Embargoed release at 11:00 a.m. PT/2:00 p.m. ET on Thursday, May 12, 2022
SEATTLE, May 12, 2022 — A new study in mice has identified FXR1, a protein from the same family implicated in fragile X syndrome, as a potential target for creating a new type of antihypertensive drug, according to research presented at the American Heart Association’s Vascular Discovery: From Genes to Medicine Scientific Sessions 2022. The meeting will be held May 12-14, 2022 in Seattle and is a leading global exchange on the latest advances in new and emerging scientific research on the arteriosclerosis, thrombosis, vascular biology, peripheral vascular diseases, vascular surgery and functional genomics.
Fragile X syndrome, or FXS, is the most common known cause of inherited 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 each year in the United States. FXS can cause developmental delays, learning disabilities, and behavioral problems, with symptoms being more severe in boys than in girls.
FXS is caused by mutations in the FMR1 gene, which codes for an RNA-binding protein FMRP that is thought 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 to see more transcription factors, translation factors, factors that regulate mRNA interaction with FXR1,” said Amanda St. Paul, lead author of study and holds a doctorate. 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 muscle contraction and relaxation.
St. Paul and his colleagues developed a mouse model where FXR1 can be deleted in smooth muscle cells – the same type that makes up blood vessels in humans. The mice were genetically modified so that the FXR1 gene could be deleted by administering the drug tamoxifen.
With the deletion of the FXR1 gene, the researchers noted that vascular smooth muscle cells behaved differently than those in mice with active FXR1.
“We found that vascular smooth muscle cells without FXR1 do not proliferate, they do not adhere, they do not migrate, activities that depend on a properly functioning cytoskeleton. And that’s all a vascular smooth muscle cell should do,” St. Paul said.
The removal of FXR1 had another eye-opening consequence: “When you remove FXR1 from the smooth muscle of these mice, they also have reduced diastolic blood pressure compared to control mice,” St. Paul said.
The analysis revealed that:
- Depletion of FXR1 decreased the ability of blood vessel cells to contract; and
- When FXR1 is deleted, mice had reduced diastolic blood pressure compared to control mice. This was measured using telemetry, an in vivo measure of blood pressure.
According to St. Paul, these results suggest that targeting FXR1 in vascular smooth muscle cells, or the contractile pathway it regulates, may be a promising avenue for antihypertensive drug development. “Many drug targets don’t focus on the cytoskeleton. Since FXR1 is muscle-specific, it gives us a specific target and pathway to look at in more detail,” she said. “Millions of people suffer from high blood pressure; it is important to find new ways to improve blood pressure.
Future work by St. Paul and colleagues will investigate whether FXR1 activity in smooth muscle cells depends on its ability to interact with cytoskeletal proteins and whether deletion of FXR1 is effective in lowering blood pressure in a hypertensive mouse model.
St. Paul received the ATVB Diversity Outreach Travel Grant for Young Investigators from the American Heart Association in April. The purpose of this award, given by the Council of Arteriosclerosis, Thrombosis and Vascular Biology, is to encourage early career minority researchers and students to participate in scientific sessions on vascular discovery: from genes to medicine.
Nearly half of all adults in the United States, as defined by the American Heart Association/American College of Cardiology 2017 High Blood Pressure Guidelines, have a systolic (upper number) blood pressure of 130 or higher mm Hg or a diastolic blood pressure (lower number) equal to or greater than 80 mm Hg, and almost. High blood pressure is a major risk factor for cardiovascular disease and stroke and increases the risk of kidney disease, vision loss and more. In 2019, more than half a million people who died in the United States had high blood pressure as the primary or contributing cause of death.
Co-authors are Kyle Preston, Ph.D.; Cali Corbett, BS; Tani Leigh, BA; Sheri E. Kelemen; Satoru Eguchi, MD, Ph.D.; Michael Autieri, Ph.D. Author disclosures are listed in the abstract.
Statements and conclusions of studies presented at American Heart Association scientific meetings are solely those of the study authors and do not necessarily reflect the policy or position of the Association. The Association makes no representations or warranties as to their accuracy or reliability. Abstracts presented at the Association’s Scientific Meetings are not peer-reviewed, but rather by independent review committees and are considered based on the potential to add to the diversity of scientific issues and viewpoints discussed. during a meeting. Results are considered preliminary until published as a full manuscript in a peer-reviewed scientific journal.