PORCN Inhibition Spurs Greater Heart Tissue Regeneration

Researchers here report on a fortuitous discovery made while searching for potential cancer therapeutics based on the suppression of mechanisms essential to growth and cellular replication, such as the Wnt signaling pathway. To the surprise of the research team, inhibition of the protein encoded by the porcupine (PORCN) gene, required for Wnt signaling, was found to spur greater heart tissue regeneration.

An anticancer agent in development promotes regeneration of damaged heart muscle - an unexpected research finding that may help prevent congestive heart failure in the future. Many parts of the body, such as blood cells and the lining of the gut, continuously renew throughout life. Others, such as the heart, do not. Because of the heart's inability to repair itself, damage caused by a heart attack causes permanent scarring that frequently results in serious weakening of the heart, known as heart failure. Researchers have worked to develop a cancer drug targeting Wnt signaling molecules. These molecules are crucial for tissue regeneration, but also frequently contribute to cancer. Essential to the production of Wnt proteins in humans is the porcupine (Porcn) enzyme, so-named because fruit fly embryos lacking this gene resemble a porcupine. In testing the porcupine inhibitor researchers developed, they noted a curiosity.

"We saw many predictable adverse effects - in bone and hair, for example - but one surprise was that the number of dividing cardiomyocytes (heart muscle cells) was slightly increased. In addition to the intense interest in porcupine inhibitors as anticancer agents, this research shows that such agents could be useful in regenerative medicine." Based on their initial results, the researchers induced heart attacks in mice and then treated them with a porcupine inhibitor. Their hearts' ability to pump blood improved by nearly twofold compared to untreated animals. Importantly, in addition to the improved pumping ability of hearts in the mice, the researchers noticed a reduction in fibrosis, or scarring in the hearts. Collagen-laden scarring that occurs following a heart attack can cause the heart to inappropriately increase in size, and lead to heart failure. Preliminary experiments indicate that the porcupine inhibitor would only need to be used for a short time following a heart attack, suggesting that the unpleasant side effects typically caused by cancer drugs might be avoided. "We hope to advance a Porcn inhibitor into clinical testing as a regenerative agent for heart disease within the next year."

Link: http://www.utsouthwestern.edu/newsroom/news-releases/year-2017/feb/heart-regeneration-lum.html

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