Scientists Uncover Mechanism of Healing an Injured Heart

Highlights:

• A mechanism of healing the heart muscle following injury discoverd
• Paves the way to develop newer and effective treatments for heart failure
• Inactivation of a cellular pathway in heart muscle cells promotes healing and repair of the heart muscle
• Treatments for heart failure must, specifically target the Hippo pathway in heart muscle cells without targeting fibroblasts, so that heart failure treatment is effective

Novel mechanism has been discovered that helps in healing the injured heart muscle. Inactivation of the Hippo cellular pathway in adult heart muscle promotes regeneration after injury. This finding is opening up avenues for research into developing promising heart failure treatments. The study was undertaken by a team of scientists at Baylor College of Medicine, the Texas Heart Institute and the University of Texas Health Science Center at Houston. The findings of the study appear in the journal Genes & Development.

Dr. James Martin, corresponding author of the study, director of the Cardiomyocyte Renewal Lab at the Texas Heart Institute and professor and Vivian L. Smith Chair in Regenerative Medicine at Baylor College, said: "Heart failure remains the leading cause of mortality in the U.S., and one of the interests of my lab is to develop ways to heal heart muscle by studying cellular pathways involved in heart development and regeneration."

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Inactivation of Hippo Cellular Pathway on Heart Function

• During previous research, the study team discovered that inactivating the Hippo cellular pathway in adult murine hearts promoted heart muscle repair and regeneration following a heart attack
• These findings were promising and paved the way to develop heart failure treatments targeting the Hippo pathway
• In the current study, the study team once again investigated the role of the Hippo pathway in the adult murine heart, focusing this time on heart fibroblasts, which are non-muscle cells found in close association with heart muscle cells (myocytes)
• During the study, the team conducted several experiments, including single-cell sequencing experiments which provided a high degree of resolution to their tests
• The studies showed that inactivating the Hippo pathway in normal resting adult hearts without stimulated activation and proliferation of fibroblasts with the formation of scar tissue or fibrosis within the heart muscle
• Mouse hearts with defective Hippo cellular pathway in heart fibroblasts spontaneously developed fibrosis and scarring of heart muscle resulting in severe heart failure

The findings of the study suggest that inactivating the Hippo cellular pathway in heart fibroblasts can cause or aggravate pre-existing failure. Therefore, heart failure treatments must, specifically target inactivation of the Hippo pathway in cardiac muscle cells.

• Additionally, the team found that inactivating the Hippo pathway resulted in a cascade of events in the cell a leading to an inflammatory response mediated by Yap, a molecule which controls several cellular pathways

"We know that Hippo and Yap work together. Hippo acts like a brake for Yap, so when we took away Hippo, Yap remained active and regulated the expression of important signaling molecules that 'talk' to macrophages and other immune cells luring them into the heart," Martin said.

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Heart Failure in Brief

• During a heart attack, the blood supply to the heart muscle is affected and therefore, they are deprived of oxygen
• As a result, the affected portion of the heart muscle undergoes infarction or dies
• The damaged heart muscle does not regenerate and instead becomes replaced with scar tissue or fibrosis, due to stimulation of heart fibroblasts
• When there is excessive scarring, the heart progressively weakens and is unable to contract and pump blood
• As a result, following a heart attack, persons can develop heart failure which is a potentially fatal condition

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Scope of the Study

• The study identifies key cellular pathways involved in heart muscle regeneration following injury and opens up future avenues of research into developing heart failure treatments
• Importantly, fibroblasts in the heart must be maintained in the inactive or resting state since activation can result in worsening of heart failure

In summary, scientists discovered a key cellular pathway, the Hippo pathway in the heart muscle, which can be specifically targeted to develop heart failure treatments in the future.

Source-Medindia