Having a big heart might have been desirable for the tin man, but as for the rest of us, not so much. Cardiac hypertrophy, thickening of the muscle tissue that comprises the heart, can force our most vital organ to work harder and cause undue stress, ultimately leading to organ failure.
Researchers at Duke University Medical Center have discovered what they believe is the signaling pathway that leads to enlarged cardiac cells. The findings from this research were published recently in Science Signaling in an article entitled “Cardiac hypertrophy induced by active Raf depends on Yorkie-mediated transcription”.

“Our finding helps us to better understand how the human heart responds to disease,” said Matthew J. Wolf, M.D., Ph.D., associate professor of medicine at Duke University School of Medicine and senior author on the study. “The question remains, why does it choose to add on mass rather than proliferate new cells? If we could solve that riddle, then we could find ways to manipulate the system to help hearts heal after injury.”

Previous work, conducted on the fruit fly Drosophila melanogaster, has shown that when researchers deleted the protein kinase gene named Hippo they were able to generate flies with unusually large organs. Conversely, deleting the transcriptional coactivator Yorkie, led to flies with extremely small organs.

Based on those findings, Dr. Wolf and his team wanted to try and find the signals that control these pathways. They were successful in discovering a molecular switch, the serine/threonine kinase Raf, which turns the Yorkie gene on to make the hearts within the fruit flies enlarge considerably. While humans undoubtedly do not look anything like fruit flies, there has been enough evolutionary conservation at the genetic level to give the researchers a unique insight into this disease. 

Drosophila has a small tube composed of a single chamber and approximately 104 cardiac cells that make up its heart. Dr. Wolf’s team was able to visualize their genetic modifications on the fruit flies using a method called optical coherence tomography, which acts much like an echocardiogram. When the team activated the Yorkie gene they were able to observe that the hearts of the mutant flies were thicker than normal, creating a much smaller chamber for blood to be pumped through.

Interestingly, when they dissected the cardiac tissue from the mutant flies they noticed that there was no change in proliferation of the cardiac cells, indicating that the cells had just grown larger.

The Wolf team is now focusing on other animal models to see if they can reproduce similar results to what they observed in Drosophila. They have already acquired a number of transgenic mice and plan to manipulate the Raf and Yorkie genes in order to measure the cardiac outcome.

“Ultimately, our goal is to try to understand how this pathway influences cardiac hypertrophy, not only within the context of specific conditions like Noonan syndrome, but also in the more general context of hypertension and high blood pressure, with the hopes of finding new targets to treat this disease,” stated Dr. Wolf.

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