Researchers discover potential therapeutic target to control scarring caused by heart attack
While studying a number of proteins that might be involved in new blood vessel formation in the heart, researchers at Cornell University and the University of Wisconsin-Madison have “accidentally” discovered that blocking a specific protein in mice reduces the permanent tissue scarring caused by a heart attack, a finding they believe could lead to the development of a therapeutic target for treating heart attack patients.
NEW YORK—While studying a number of proteins that might be involved in new blood vessel formation in the heart, researchers at Cornell University and the University of Wisconsin-Madison have "accidentally" discovered that blocking a specific protein in mice reduces the permanent tissue scarring caused by a heart attack, a finding they believe could lead to the development of a therapeutic target for treating heart attack patients.
After publishing their findings in the Dec. 14 online edition of Nature Cell Biology, the researchers are seeking a commercial partner to examine whether the protein sFRP2 could serve as a therapeutic target to control fibrosis. According to the study's senior author, Dr. Thomas N. Sato, a professor in the Department of Cell and Developmental Biology at Cornell's Weill Medical College, this potential target could facilitate the restoration of the contractile function of a damaged heart following a heart attack.
"Our result clearly shows that sFRP2 could be a potential therapeutic target for treating the heart attack patients," Sato says. "Some therapeutic methods to inhibit sFRP2 function could bring a great benefit to many patients who had or will have heart attacks. We are currently seeking collaborators in pharmaceutical industry who would like to work together with us to develop such therapeutic methods based on our discovery."
In their research efforts, the scientists "accidentally" found that the sFRP2 protein's expression is induced during the fibrosis phase in the heart after myocardial infarction.
"Upon myocardial infarction, a large number of contractile myocytes die," Sato explains. "It is a natural defense mechanism for the heart to develop fibrosis to fill the space where the myocytes died. Without fibrosis, the cardiac wall becomes so fragile and the heart raptures as it cannot withstand the blood flow. However, in the normal course of disease, the fibrosis occurs excessively, resulting in scar tissue formation and making the heart very hard like steel. Thus the heart can no longer pump the blood properly. Furthermore, such fibrosis prevents the damaged heart from generating or regenerating new myocytes."
Hypothesizing that sFRP2 may play some important role in fibrosis, the scientists removed a gene encoding sFRP2 protein in mice by a genetic engineering method and surgically tied the coronary artery of the mice's hearts, mimicking the situation of heart attack in human. The mice exhibited a lesser degree of fibrosis compared to genetically normal mice that had the same surgical procedure.
"Our study shows that, in the absence of sFRP2, the infarcted heart deposits some collagen fibers, but not excessively," Sato says. "Thus, it is possible that some chemical inhibitor(s) of sFRP2 protein function could be used to not totally inhibit collagen deposition, but limit the degree of collagen deposition."
Current therapies focus on regenerating myocytes after myocardial infarction to restore the cardiac function by using stem cells and/or drugs, but these regenerative medicine approaches fail unless one can remove excessive fibrosis, Sato says.
"For this reason also, it is important to reduce the level of fibrosis, and our study shows that sFRP2 could be such a therapeutic target," he says.
But Sato notes that limiting the degree of fibrosis alone does not solve all the medical problems caused by a heart attack. The researchers will further study the pathogenic processes that occur after a heart attack—especially at the molecular level—in order to design the most effective therapeutic methods to facilitate the recovery of a damaged heart after heart attack, he says. The researchers will also study whether sFRP2 could play a role in the fibrosis phase of other diseases such liver and lung disease.
"With our genetically engineered mice, it is certainly possible for us to examine whether sFRP2 plays an important role in fibrosis in such other disease conditions," Sato says. "Fibrosis occurs in a number of other diseases such as hepatitis, another major disease in our society. Fibrosis is also a problem in other diseases in kidney and lung. Therapeutic methods to limit the degree of fibrosis in such other diseases could bring some benefit to improve the patients' health conditions. However, at the moment, we do not know whether sFRP2 protein is present during the fibrosis phase in these other diseases."
The study, Secreted Frizzled-related protein 2 is a procollagen C proteinase enhancer with a role in fibrosis associated with myocardial infarction, was co-authored by the departments of Pathology and Laboratory Medicine and Pharmacology at the University of Wisconsin-Madison. DDN