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Researchers at the University of Michigan say they can help people with heart disease by literally making them young at heart. As this ScienCentral News video explains, they're doing so by coaxing special compounds in adult hearts to behave the way they do in a growing fetus.
Forever Young at Heart
Most of us think we know a lot about stress, and probably with good reason. Deadlines, stubbed toes, car accidents, family feuds, burnt meals, stock market dips, bad haircuts — just to name a few of the possible daily sources of worry that can make our hearts palpitate. Fortunately, none of us remember one of the most stressful events of our lives — being born.
It turns out that we didn't get through the stress of life in the womb on good luck alone. Babies have a special kind of protection from stress that keeps their hearts beating even through difficult situations. They make a different version of a certain cardiac protein than adult hearts produce. Soon after birth, we stop making the fetal form of the protein and settle into permanently making the adult version.
image: ABC News
University of Michigan cardiologist Sharlene Day and physiologist Joseph Metzger, say the adult form of that protein, called troponin I, normally regulates how our hearts beat. It also allows our hearts to respond properly during the "fight or flight response" which we undergo when we sense imminent danger. Unfortunately though, the adult form of troponin I wasn't designed to handle bacon cheeseburgers and divorces. Partly as a consequence, heart disease is still the number one cause of death in the United States.
During a situation like a heart attack, adult troponin-I stops working properly. "In the face of this challenge of a heart attack, this troponin I molecule turns down its activity and, in effect, [shuts] off the pumping function of the heart," explains Metzger. That's largely because the conditions in the heart becomes more acidic and the troponin I no longer responds to its signals to make the heart contract normally. Instead of causing the heart to pump more strongly, it begins to slow down. The fetal form of troponin I, on the other hand, keeps responding to the contraction signals even in acidic conditions.
As reported in Nature Medicine, Metzger and Day's team found a way to improve adult troponin I by using DNA technology to make a combined fetal and adult version. Day says, "What we did was to take a very small piece of the DNA from the fetal form and insert it into the adult form." Indeed, it was a very small piece of DNA — only one amino acid. They swapped a single amino acid, called alanine, in the troponin I protein for a histidine. "Histidine is a very small piece of the protein. A protein is like a string of beads, and histidine is like one bead in that string," Day explains.
Even though it's only a very small change, the team saw dramatic results. When they put this combination protein in to mice, they discovered that the animals with the new form of troponin-I withstood heart attacks better than those with the normal adult version. "Their hearts contracted more vigorously, their hearts did not enlarge as much as the hearts of the animals that did not make the protein," Day says.
They observed a similar improvement in contraction when, in the lab, they put the new protein into human heart cells taken from patients with heart disease. "These were cells that we obtained from patients undergoing heart transplantation. So these were very sick patients — the cells as a result were very weak," she says. "And we were able to introduce this new troponin I protein into those heart cells and make them beat stronger and enable them to beat at a faster rate."
Even when there's nothing wrong in the heart, this combined version of the protein functions normally. It even maintains the proper response to the fight or flight response that adult hearts normally have. The only situation in which it behaves differently is during heart failure. "It serves as a sensor function, much like a smoke detector does in your home," Metzger says. "It's waiting there, like a guardian, in effect sensing if there's a change in the environment of the cell." It's only in situations where the heart becomes acidic, and the normal troponin I fails, that you see the difference in how this newly-engineered version works.
Day and Metzger say that there are several hurdles to overcome before this modified troponin I becomes available to treat people. Since this is a gene therapy, one of the biggest problems will be to figure out how to get this modified protein into the hearts of patients. Until the team figures things out, we'll just have to keep our hearts young and healthy in the usual ways — exercising, eating right, and trying to keep our dose of daily stress to minimum.
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