TENASCIN-C HELPS DIRECT CLOT-INDUCED NEOVASCULARIZION.
The discovery that the molecule, called tenascin-C, helps direct clot-induced cardiac neovascularization solves a 30-year-old medical riddle. It also opens the door to new ways of preventing and treating heart attack and stroke.
"Agents that target tenascin-C might someday be used to enhance the body's natural capacity to break down blood clots, or even prevent them," explained Dr. Jay M. Edelberg, Associate Professor of Medicine and Cell and Developmental Biology at Weill Cornell Medical College, and a cardiologist in the Greenberg Division of Cardiology at NewYork- Presbyterian Hospital/Weill Cornell Medical Center, in New York City.
Although this paper marks a real breakthrough, medical science is no stranger to tenascin-C.
"We've long known that this molecule resides in the bone marrow and also appears at sites of injury, in association with new blood vessel formation. We therefore hypothesized that tenascin-C in the bone marrow might be helping to direct the activity of stem-cell-like endothelial progenitor cells," explained lead researcher Dr. Victoria L. T. Ballard, Postdoctoral Fellow in Medicine at Weill Cornell Medical College. "These cells fan out into the body and contribute to the building of new blood vessels."
But experts have also known that local progenitor cells in and around the heart swing into action when cardiac tissue is threatened or damaged by a clot.
"Two things happen: fibrinolytic enzymes try and break the clot down, but, at the same time, the body uses progenitor cells to help form new channels that cut through the clot to break it up and permit blood flow -- in other words, neovascularization," Dr. Ballard said.
Just how this local process was directed remained a mystery.
However, in studies conducted both in mice and in heart attack patients, the Weill Cornell team discovered that tenascin-C also reappears in and around the heart to help guide clot-induced neovascularization.
"Tenascin-C seems to instruct this process, much as it does for progenitor cells in the bone marrow," Dr. Edelberg said. "So, it's in the bone marrow -- where endothelial progenitor cells originate and now we've found that it pops up temporarily when clots endanger the heart."
"It's a real surprise, and the first mechanism we've come across that could explain this phenomenon," he added.
In the mice studies, rodents genetically engineered to lack tenascin-C showed no evidence of neovascularization, suggesting the protein is crucial to the process.
Even more exciting was "translational" research involving patients experiencing a heart attack caused by a clot. The patients were treated as per usual in the Hospital's cardiac catheterization lab.
"We removed the clot with a catheter," said study co-author Dr. Shing-Chiu Wong, director of the Cardiac Catheterization Laboratory at NewYork-Presbyterian/Weill Cornell. "Under closer inspection, we discovered the unexpected presence of tenascin-C in the clot. The body appeared to be using the protein to initiate and direct the breakdown of the clot through the formation of tiny new blood vessels."
The bottom line: Tenascin-C appears to guide endothelial neovascularization, not only from its "home base" in the marrow, but also in clots that threaten the heart.
"It's like a general giving instructions to the troops during training, then reinforcing those instructions at the site of battle," Dr. Edelberg said.
The finding has major implications for stroke prevention and treatment, the authors said.
"Tenascin-C is a big molecule, so our next step is to find appropriate binding sites -- molecular 'hooks' for agents that might enhance this protein's activity," Dr. Ballard said.
In terms of prevention, the researchers say drugs might someday be developed that could keep tenascin-C on "high alert," improving its ability to destroy clots before they do major harm.
For more major clots, tenascin-C-enhancing drugs might boost natural anti-clotting processes that kick into gear during cardiac crisis.
The researchers point out that the powerful clot-busting drug tissue plasminogen activator (tPA) works on a similar overall principle. The medication which saves thousands of lives each year in the U.S. -- works by boosting the body's enzymatic response to dangerous clots.
Tenascin-C's newfound role offers up similar possibilities, directing the body's own cells to break through blood clots.
"This discovery should give us brand-new weapons against clot-induced stroke and heart attack," said co-author Dr. Katherine A. Hajjar, chair of the Department of Cell and Developmental Biology at Weill Cornell. "It's really an exciting new frontier."
This work was funded, in part, by a Charles E. Culpeper Scholarship in Medical Science from the Rockefeller Brothers Fund and grants from the National Institutes of Health.
Co-authors include Dr. Arti Sharma, Inga Duignan, Jacquelyne M. Holm, Andrew Chin, and Ruby Choi -- all of the Weill Medical College of Cornell University, New York City.
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