Researchers have discovered how to turn off a key driver of aortic stenosis the narrowing of the hearts aortic valve identifying for the first time the biological process behind certain instances of the disease in which heart valves become calcified and damaged.
The research was reported Nov. 5 in Science Advances, and the breakthrough was over a decade in the making for the studys co-author Jonathan Butcher, professor of biomedical engineering.
Since 2009, Butcher has been studying cells essential for embryonic development of the cardiovascular system. Wanting to show what a subset of those cells would do in a disease state, he published a 2012 study finding that a specific type of inflammation can trigger the cells to undergo the same biological process as they do in the development stage.
Developmental biology used to be studied completely separate from adult disease because they were seen as driving two completely different systems, Butcher said. More recently, theres been the idea that molecules that drive tissue formation might also be involved in forming a tissue-level response to an external stimulus like a disease.
In the case of the cells responsible for heart valve development and disease, Butcher wanted to know more about their shared regulatory component.
Butcher was presenting his work at a research consortium in which another researcher, Michel Puceat from Aix-Marseille University, shared research on a natural biological program in adult mouse heart valves known as OCT4, which Butcher recognized as an early development program and was surprised to see in adult subjects.
The researchers agreed to work together, doing molecular gain and loss of function studies to show that OCT4 switches off very early in embryonic development, but can be turned on later in adulthood. What flips the switch is the inflammatory transcription factor NF kappa B the same one Butcher had studied a decade ago but this time, the OCT4 program was operating a different lineage of cells.
We found this nascent ability of the cells to form bone thats suppressed in the embryonic environment, Butcher said, but in the adult disease environment, its now amplifying that nascent desire to become an osteochondral progenitor.
Essentially, inflammation can switch on dormant embryonic programming in adult cells, and the disease environment leads them to behave differently and calcify the heart valve, causing aortic stenosis.
For the last portion of the study, the researchers wanted to see if they could prevent stenosis in mice by genetically deactivating the OCT4 program after its embryonic role was finished. The experiment was successful, and mice with OCT4 deleted in pro-valve tissue resisted the disease despite having the genetic risk factor and a high-fat, inflammation-inducing diet.
The difference was remarkable and it suggests this particular mechanism could be a pretty safe way to treat the disease because you're not going to worry about disrupting a whole bunch of other things, said Butcher, who added that there are several options for exploring a therapy for humans. We might be able to block it with anti-inflammatory drugs that stop the switch operator, or it might be safer to block it by manipulating this transformation component downstream.
Butcher said the research is an example of observing and targeting emergent phenomena by going beyond the traditional method of studying individual cells and molecules as disease drivers, and instead observing the relationships between components.
This particular work to me was something that really engaged the ingenuity of a lot of people, Butcher said. This concept of emergence will be critically important for developing next-level therapy for diseases.
The research was funded by the Leducq Foundation, the National Institutes of Health and the National Science Foundation.
Syl Kacapyr is public relations and content manager for the College of Engineering.
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