A study led by University of Iowa researchers has revealed a key enzyme that may shed light on why heart cells die in a person with heart disease. Mark Anderson. MD, PhD director of the UI Division of Cardiovascular Medicine at University of Iowa Hospitals and Clinics and senior author of the study, talks about the study:
What departments and institutions assisted with this research study?
This was a complicated study and it involved the participation of many talented and hard working people. The core group was in the Department of Internal Medicine here at The University of Iowa, but the study also involved folks from the Oxygen Radical Group, from the Microscopy Core, from the Department of Molecular Physiology at Vanderbilt University, and others.
Why is the collaboration of so many departments within the UI and other institutions beneficial in a study like this?
It's simply because the kinds of expertise, the ability to look at a problem in many different ways, cannot reside in one or even a few people. The way the scientific departments have grown at The University of Iowa means there is a diverse assortment of expertise we can draw on. Because of the collaborative nature of individuals within the institution, it makes these complicated studies possible and even enjoyable to perform.
What was the purpose or intent of the study?
The intent of the study was to understand how disease stresses cause heart muscle cells to die, particularly in the setting of a heart attack or a myocardial infarction and under conditions of heart failure—both common and lethal types of disease that are distressingly common in Iowa and in the United States.
We took a very molecular focus and examined calmodulin-dependent kinase (CaMKII), a molecule that my laboratory has tracked now for about a decade to define a new molecular mechanism for how this molecule is activated.
We know that in heart disease and cancer and some neurological diseases, one of the stressors, or problems, appears to be too much oxidation—the same process that is involved in rusting metal. We found that oxidation modifies this enzyme at at two molecular sites and that that can be reversed through another enzyme. We identified these sites and the molecular mechanism and then marked this new enzyme that reverses that process as a potential means of therapy in this kind of heart disease.
It's interesting to note that this other mechanism that reverses the rusting of CaMKII was identified by some people in the National Academy of Science several years ago as a molecule that determined the lifespan of mice and simpler animal models like worms and flies, but nobody knew what the targets were. This work identifies CaMKII as a key target in a survival pathway. And because heart disease shortens survival, this mechanism may be important for a wide range of patients in the United States and in Iowa.
How was the study carried out—in lab or clinic?
This work was done exclusively in the lab, but our clinic. For purposes of this research, our patients are mice. People are sometimes surprised to think that doing research on mice might teach us what would be of value for people.
It turns out time and time again, that mice have led the way into developing insights for treatments for patients. It's worth noting that a mouse heart, although about the size of a plain M&M, is an exact replica (albeit scaled down) of a human heart and that the molecular signals and the processing that works in a mouse heart appear to largely parallel that which happens in human hearts.
By being able to do very detailed studies and manipulate the genes and the molecules in the heart in a way that could never be done by people, we can get a first glimpse into pathways that will be important for human disease.
How would you describe the study's findings to a patient or their family?
This study gives us new information that suggests why they should take some of the medicines they may already be taking, beta blockers and ace inhibitors. It also provides the hope that new medicines to specifically inhibit CaMKII may be available in the future and that those would allow for better performance of hearts after a heart attack.
What are the implications of the study for people with heart failure or arrhythmias?
The implications are that both of those conditions can be lethal and lead to a significant amount of deaths across the country. Science has provided an excellent pathway for developing therapies that have led to increased lifespan and improved quality of life. I think our study shows that this pathway is still strong; that the road of scientific discovery is active and likely to produce new and improved therapies in their lifetimes or in the lifetimes of their children.
What are the next steps in this study?
We sent one of our investigators to Holland to screen the universe of heart proteins to see how it would interact with our molecule. And then we began making a new mouse that will have a rust-resistant form of CaMKII, and also interbreeding these mice with other kinds of genetically-modified mice to really track down how important CaMKII is in the hierarchy of all potential rustable proteins.
How long might it take for the results of this study to be used in clinical practice?
I think that it may take a decade. People are often frustrated that it's not sooner, but when you think about how heart attacks were treated 20 years ago—there really were no specific treatments and now there are a plethora of treatments. The time course of a decade is fast. We would like it to be faster, but I think that a decade is realistic.
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