Dr. Barbara Ranscht is a neuroscientist. While studying brain development and cancer for more than 20 years, she has come to know a molecule called T-cadherin. This protein is anchored to the cell membrane, where it senses changes in the extracellular environment to ultimately regulate cellular motility and growth. T-cadherin has multiple functions in the nervous system, but when she first discovered this protein in the 1990s, Dr. Ranscht also noted its abundance in the heart. For many years Dr. Ranscht paid little attention to the molecular workings of the heart, preferring to stick to the mysteries of the brain. Until recently, when she came across new clues about T-cadherin and its possible role in protecting the heart from stress-induced damage. At that point, most researchers would probably have let go of the idea rather than jump into a new field.

Luckily, Dr. Ranscht goes kickboxing with her colleague, friend and heart expert, Dr. Pilar Ruiz-Lozano.

“Being stressed, we needed to re-direct our energy into positive movements. We were coming back from kickboxing class one day and started talking,” Dr. Ranscht explains.

The researchers discussed a hormone called adiponectin and Dr. Ranscht’s idea that T-cadherin might play a role in protecting the heart. Adiponectin is a metabolic hormone produced by fat cells and shed into the bloodstream. Healthy people usually have high levels of adiponectin circulating in their bodies, while low adiponectin levels correlate with diabetes, heart disease, stroke and other problems. Given the current obesity epidemic in the United States, adiponectin is a hot topic. Yet, nobody really knew how this circulating hormone protects against cardiac disease – not even how it’s initially attracted to the heart.

“I knew Pilar as a heart expert”, Dr. Ranscht recalls. “I presented her with the idea that T-cadherin could be the receptor that is necessary for adiponectin’s protective functions in the heart and emphasized that I would love to test this possibility in our mouse model. Pilar just looked at me and said: ‘We can do this!’”

And so a fruitful collaboration was born. The best way to determine T-cadherin’s role in heart protection is to see what happens when the protein is missing.  Dr. Martin Denzel, then a graduate student in Dr. Ranscht’s laboratory, was enthusiastic about this project.  With the help of others, he looked at the hearts of mice engineered to lack T-cadherin, and found that adiponectin was no longer able to bind to heart tissue, leaving more hormone floating in the bloodstream. However, the mutant mouse hearts still functioned normally. At least initially…

Rather than giving up when they saw no difference in function between mouse hearts with and without T-cadherin, cardiologist Dr. Maria Cecila Scimia suggested they stress the heart by restricting blood flow. With her expertise, the team found increased damage, such as occurs after a heart attack, in hearts lacking T-cadherin (and therefore lacking adiponectin, too). The T-cadherin-deficient mice experienced the same symptoms under those conditions as mice without adiponectin. Even when the team attempted to “rescue” mice lacking both T-cadherin and adiponectin by adding in extra adiponectin, no benefits resulted, underscoring T-cadherin’s necessity for mediating adiponectin functions in the heart.

Thus, by accepting the risk that comes with stepping outside the box, the team around Drs. Ranscht and Ruiz-Lozano made waves in the heart field this week. Their paper, with Dr. Martin Denzel as the lead author, appeared in the Journal of Clinical Investigation on November 1. There, they convincingly demonstrate that T-cadherin is indeed adiponectin’s long-sought link to heart cells.

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Original paper:
Denzel, M., Scimia, M., Zumstein, P., Walsh, K., Ruiz-Lozano, P., & Ranscht, B. (2010). T-cadherin is critical for adiponectin-mediated cardioprotection in mice Journal of Clinical Investigation DOI: 10.1172/JCI43464