Heart Disease :: Growth factor TGF-beta repairs heart function
Two research teams tricked one of the body?s growth factors into helping the heart repair itself after a heart attack, according to reports in Circulation: Journal of the American Heart Association.
Transforming growth factor (TGF)-beta is a cytokine, a protein that regulates immune response and mediates communication between cells. TGF-beta is released from cells in response to many different stimuli, including stress, with effects that can be either beneficial or deleterious for heart cells.
One team of researchers, led by Kimikazu Hamano, M.D., and colleagues at Yamaguchi University School of Medicine in Ube, Japan, took advantage of the good effects, using TGF-beta to coax bone marrow cells into becoming cardiac cells.
First isolated more than 20 years ago, TGF-beta was identified from sarcoma (cancer) cells and can promote new growth of fibroblasts, which are a type of skin cell. TGF-beta has also been linked to a wide range of biological processes, including proliferation and remodeling of heart cells.
During a heart attack, plaque and blood clots block blood vessels in the heart. Just as water can no longer flow through a plugged pipe, oxygen- and nutrient-rich blood can no longer reach heart cells, causing the cells to die. Scar tissue, or fibrosis, forms in areas of cell death.
The heart starts undergoing a process called remodeling to compensate for the dead cells.
The cells get bigger – a process called hypertrophy – and the heart enlarges because a bigger organ doesn?t have to squeeze as hard to do the same amount of work. Over time, however, an enlarged heart can lead to heart failure.
The second team led by Hisayoshi Fujiwara, M.D., Ph.D., and colleagues at Gifu University School of Medicine in Yanagido, Japan, harnessed the protein?s bad effects to improve heart function in mice by blocking TGF-beta and slowing the damage associated with a heart attack.
Like a key and lock, TGF-beta has to bind to a receptor to do its work, so the researchers created an artificial TGF-beta receptor with a similar structure to the real thing that can also bind the protein.
On the third day after a heart attack, the researchers used gene therapy to deliver the artificial TGF-beta receptor to mice, inhibiting the function of TGF-beta. The fake receptor grabs the circulating protein out of circulation so it can no longer exert its negative effect.
Unexpectedly, it was found that inhibition of TGF-beta directly protected cells in heart tissue damaged from blockages in the heart, Fujiwara said.
Many heart attack patients miss the chance for coronary intervention because to be effective it must be performed within a few hours after the onset of a heart attack, Fujiwara said. After this golden time has passed, there is no active therapy for patients at present. Our findings imply a new therapeutic strategy that is applicable even to the people who missed this golden opportunity.
Hamano used TGF-beta to improve blood flow to the heart. They withdrew bone marrow from mouse thigh and shin bones. From this harvested marrow, they prepared a mixture rich in stem cells. Stem cells are progenitor cells that can grow into specialized cells in the body, such as heart, nerve or organ cells.
These stem cells were pre-treated with TGF-beta for 24 hours, and then injected into the hearts of mice that had been induced to have heart attacks.
Within three months, mice that were injected with the TGF-enriched stem cells showed marked improvement in blood flow to the parts of their heart that were treated. Results of the tests indicated that there was new blood vessels formed by this treatment. There was less scar tissue in the treated area, Hamano said. Furthermore, about 30 percent of the TGF-enriched stem cells had differentiated into heart muscle cells, he said.
Most importantly, the mice had gotten better, Hamano said. Heart function, as assessed by echocardiography, had improved.
In an accompanying editorial Ronglih Liao, Ph.D., co-director of the Cardiac Muscle Research Laboratory at the Whitaker Cardiovascular Institute in Boston, noted that, While no one knows how one protein can be both a bad guy and good guy, the research suggests that timing is everything. Early on, TGF-beta seems to be a good thing, but after that window passes, it becomes deleterious and you want to block it. Within the first 24 to 72 hours following cardiac injury, locally released TGF-beta 1 may promote regeneration, but after this stage it may be detrimental.
When you give a treatment, you have to be very careful about the timing, Liao said.