They found that silencing a signaling pathway in mice that had developed heart failure following a heart attack activated a previously unrecognized self-healing process.
In a paper recently published in the journal Nature, the researchers, led by a team from Baylor College of Medicine in Houston, TX, report their findings about the signaling pathway, which is known as Hippo.
Heart failure is a serious condition that affects around 5.7 million adults in the United States. It develops when the heart cannot pump enough blood to meet the body’s needs.
Heart failure does not mean that the heart has stopped pumping, but it does mean that vital organs do not get the oxygen and nutrients they need to function properly. Around half of patients with heart failure do not live more than 5 years after diagnosis.
“Heart failure remains the leading cause of mortality from heart disease,” explains corresponding author James F. Martin, a professor who specializes in regenerative medicine at Baylor College of Medicine and who is also director of the Cardiomyocyte Renewal Lab at the Texas Heart Institute, also in Houston.
Injured hearts favor scarring to regeneration
At present, the best treatment for heart failure is a heart transplant. However, the number of heart failure patients far exceeds the number of hearts available for transplant. Having a ventricular assist device implanted is also an option, but it is a much less favorable one.
One of the curious things about heart muscle is that it does not regenerate when it dies after being starved of oxygen, such as after a heart attack.
Instead of generating new beating muscle cells, or cardiomyocytes, the heart replaces the dead tissue with scar tissue made from fibroblast cells.
Unlike cardiomyocytes, fibroblasts have no pumping ability, so the heart gradually gets weaker and weaker, with the result that the majority of severe heart attack patients develop heart failure.
Prof. Martin says that he and his laboratory team are studying biological pathways that are active during heart development and regeneration in order to find ways to heal heart muscle.
Biological pathways are series of molecular events inside cells that lead to changes in the cell or result in particular products. For example, they can turn genes on and off and they can trigger cells to make fats, proteins, hormones, and other molecules. They can also carry signals and cause cells to move.
Silencing the Hippo pathway
“In this study, we investigated the Hippo pathway, which is known from my lab’s previous studies to prevent adult heart muscle cell proliferation and regeneration,” Prof. Martin notes.
In their study paper, he and his colleagues explain that the Hippo pathway – “a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration” – is more active in patients with heart failure.
“This,” says first author John Leach, a graduate student of molecular physiology and biophysics in Prof. Martin’s group, “led us to think that if we could turn Hippo off, then we might be able to induce improvement in heart function.”
So, the team silenced the Hippo pathway in a mouse model that mimics the type of advanced heart failure that occurs in humans after a heart attack. They compared the results with those of a group of healthy mice (the controls).
“After 6 weeks we observed that the injured hearts had recovered their pumping function to the level of the control, healthy hearts,” says Leach.
The researchers believe that silencing Hippo not only renews heart muscle cells – as investigated extensively in their study – but it also changes the process of fibrosis, or scarring. They call for further studies to investigate the effects on fibrosis.