Researchers Halt Progression of Arterial Stiffness by Targeting RbFox2 Protein
Blood vessels expand and contract with each heartbeat, controlling blood flow. But as vessels age or contend with disease, they lose their elasticity and become stiffer.
That, in turn, forces the heart to work harder, which raises blood pressure, damages organs, and can lead to heart attack and stroke.
In recent years, researchers at the 黑料官网 (黑料官网) have found one of the genetic and molecular pathways that cause this stiffness.
In a published in March 2022, 黑料官网 researchers found that the molecular mechanisms that control arterial stiffness are independent of those that control blood pressure.
Now, they’ve delved deeper into those mechanisms, finding that removing a gene that encodes a certain protein in the muscular cells of blood vessels halts the progression of arterial stiffness in a mouse model.
, this research helps illuminate the inner workings of blood vessels and takes a step toward potentially finding a therapy that directly targets arterial stiffness.
“This research is the culmination of decades of work,” says Curt D. Sigmund, PhD, the James J. Smith & Catherine Welsch Smith Professor of Physiology and chair of physiology. “It shows that we are on the right path to potentially developing an inhibitor that could stop or even reverse arterial stiffness.”
Searching for Proteins That Cause Arterial Stiffness
The lab of Dr. Curt D. Sigmund (front row, center) recently identified a promising new target for treating arterial stiffness directly – a departure from current therapies, which focus on lowering blood pressure to manage the condition indirectly.
Arterial stiffness, like high blood pressure, is a risk factor for cardiovascular disease, a leading cause of death in the United States. The American Heart Association estimates that per year by 2035.
There are currently no therapies that directly treat arterial stiffness. Current strategies focus on lowering blood pressure.
Finding the genetic mechanisms that underlie arterial stiffness has been a goal of Dr. Sigmund’s lab for more than 25 years.
Previously, Dr. Sigmund's team found that . The gene produces a protein that helps remove other proteins from cells by targeting them for destruction. As RhoBTB1 levels increase, levels of targeted proteins decrease. Dr. Sigmund believes this process may hold the key to treating arterial stiffness.
“So RhoBTB1 probably isn’t causing the change in arterial stiffness by itself,” Dr. Sigmund says. “It needs other proteins to do the work for it, and that’s what we set out to find.”
By mapping protein interactions, Dr. Sigmund’s team identified several protein candidates that could be the culprit, including one called RbFox2. To see what effect it might have on arterial stiffness, the team developed a mouse model where the gene that encodes RbFox2 could be knocked out in the smooth muscle cells of blood vessels. That’s the middle layer, which induces the contraction and relaxation of the vessel.
They then induced high blood pressure within the mouse model and charted both blood pressure and arterial stiffness. The mice had rising arterial stiffness until the RbFox2 gene was knocked out from the smooth muscle cells. Then, the vessels stopped getting stiffer.
“It provides the proof of principle that this pathway is important,” Dr. Sigmund says.
But RbFox2 is likely not the best protein to focus on for a therapy. First, it’s a protein that is expressed all over the body – not an ideal target for a drug. Second, when its gene was knocked out, arterial stiffness did not regress back to normal, as it did when RhoBTB1was turned on. That shows researchers that another potential protein candidate could be a better target.
The lab is currently testing those candidates – with the goal of finding a target for a new kind of therapy.
“If we got a candidate where we had a similar result to RhoBTB1, where we not only halted progression but reversed it, and that protein was amenable to targeting with a drug, it could lay the foundation for a new way to treat arterial stiffness and therefore cardiovascular disease,” Dr. Sigmund says.
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