New study provides insight into how congenital heart defects manifest

August 2, 2022 — About one percent of the world’s population is born with a congenital heart defect, which affects about 40,000 births in the United States each year, but how these particular birth defects occur is largely unknown.

In an effort to learn more about how the heart develops, researchers at the University of Maryland School of Medicine (UMSOM) have determined that the cells that line the heart direct the heart muscle to grow. until the heart reaches its maximum size. They also described the complex mechanism that regulates this process, which requires bypassing two sets of brakes for the heart to develop properly.

The researchers say these findings explain a little more about what can go wrong during development that can lead to congenital heart defects and may also help develop better techniques for regenerating heart tissue.

“To recover from disease, you have to understand how to do heart regeneration. Currently, no one can regenerate an entire heart, mainly because they have focused on using heart muscle to grow more hearts. heart muscle cells,” said Deqiang Li, PhD, assistant professor of surgery at the University of Maryland School of Medicine in the Center for Vascular and Inflammatory Diseases. heart, such as the epicardium (the cells that line the heart), to provide the necessary instructions for the heart muscle to grow.”

The mechanism described by the team was published June 20 in Circulation Research.

The gene regulatory histone deacetylase 3 (HDAC3, for short) was known to be important for the development of heart muscle cells, but whether it played a specific role in the distinct layer of cells that line the heart was unknown. To explore the role of HDAC3 in heart development, researchers genetically engineered mice to only lack HDAC3 in the cells that line the heart. In fetal mice, they found that those hearts without HDAC3 in the cardiac lining had thinner, more compact walls in the heart ventricles – basically, it looked like the hearts weren’t growing enough.

The research team determined that cells lining the heart without the HDAC3 gene regulator also produced fewer of two growth factors than these cells normally pump to promote cardiac growth, while producing too many of two microRNAs. MicroRNAs are small pieces of genetic material that control which genes are turned on and turned into proteins.

“We struggled for a long time to put the pieces of this mechanism together. One day, the postdoctoral fellow and lead author of the study, Jihyun Jang, PhD, approached me and expressed the brilliant idea of ​​double braking mechanisms of microRNAs preventing the manufacture of growth factors, which turned out to be finally turned out to be true! says Dr. Li. “We would not have been able to complete this study without the valuable contributions and insights of our co-authors, as well as the support of the Department of Surgery and the Center for Vascular and Inflammatory Diseases.”

Separately, they found that HDAC3 turns off the genes that code for the two microRNAs, allowing growth factors to be generated and ensuring the heart grows to full size.

“You might be wondering, why use such a complicated strategy that requires crossing two double brakes for a normal heart to develop? Well, gene regulators like HDAC3 are found in every cell in the body, and microRNAs are also found everywhere. These specific regulatory hurdles make it possible to specialize this process in various places in the body. Of course, this also means that these cellular mechanisms may also have applications for other diseases, such as cancer,” said Dr. Li “To some people, this mechanism and these results can seem incredibly detailed. If you think about life, the details matter. If one little thing goes wrong, then everything goes wrong.”

E. Albert Reece, MD, PhD, MBA, Vice President for Medical Affairs, University of Maryland, and John Z. and Akiko K. Bowers Professor Emeritus and Dean, University of Maryland School of Medicine, said: “One of the health conditions that I’ve spent much of my career studying are the mechanisms behind structural birth defects. Basic research, as carried out in this study, is essential for us to know how the body develops normally, so that we can determine what is wrong with disease, and eventually one day, in this case, we can find ways to prevent congenital heart defects in the next generation of newborns.

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