News 2022 – New study provides insight into how congenital heart defects manifest

Findings from the University of Maryland School of Medicine demonstrate that the cells that line the heart determine the size of the heart

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

    Deqiang Li, PhDIn 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 illness, 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 heart muscle cells,” said Deqiang Li, PhDassistant professor of surgery at the University of Maryland School of Medicine in the Center for Vascular and Inflammatory Diseases. “Our results suggest that we may need other cells in the heart, such as the epicardium (the cells that line the heart), to provide the necessary instructions for heart muscle to grow.”

The mechanism described by the team was published on June 20 in Traffic 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 plays a specific role in the separate 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 heart’s lining had thinner, more compact walls in the ventricles of the heart — 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 the two growth factors that these cells normally pump to promote heart 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.

When the cells that line the heart lack HDAC3 (bottom), the mouse heart develops thinner and more compact walls in the ventricle compared to normal mouse hearts (top).  Credit: Broadcast ResearchWe have struggled for a long time to put the pieces of this mechanism together. One day Postdoctoral Fellow and Study Lead Author Jihyun Jang, PhD, approached me and expressed to me the brilliant idea of ​​double braking mechanisms of microRNAs preventing the manufacture of growth factors, which ultimately turned out to be true! said 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 reaches normal 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 locations 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 may 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, MBAE. Albert Reece, MD, PhD, MBAUniversity of Maryland Vice President for Medical Affairs, John Z. and Akiko K. Bowers Professor Emeritus and Dean of the University of Maryland School of Medicine, said: “One of the health issues that I have spent much of my career studying is the mechanisms behind structural birth defects. Basic research, as performed in this study, is essential for us to know how the body normally develops, so we can figure out what’s wrong with disease, and eventually one day, if so, we can find ways to prevent congenital heart defects in the next generation of newborns.

Other authors include visiting postdoctoral researcher Guang Song, MD, PhD; lab technician Sarah Pettit; Postdoctoral Fellow Qinshan Li, MD, PhD; Visiting Student Xiaosu Song, MD, PhD; and Sunjay Kaushal, PhD, MD, professor of surgery, all from the University of Maryland School of Medicine; and Chen-leng Cai, PhD, of Indiana University.

This work was supported by the National Heart, Lung, and Blood Institute (grant R01HL153406) and start-up funds from the Department of Surgery, University of Maryland School of Medicine.

About University of Maryland Medical School

Now in its third century, the University of Maryland School of Medicine was incorporated in 1807 as the first public medical school in the United States. It continues today to be one of the world’s fastest growing leading biomedical research enterprises – with 46 academic departments, centers, institutes and programs, and a faculty of more than 3,000 physicians, scientists and allied health professionals, including members. of the National Academy of Medicine and the National Academy of Sciences, and a two-time distinguished recipient of the Albert E. Lasker Award in Medical Research. With an operating budget of more than $1.3 billion, the School of Medicine works closely with the University of Maryland Medical Center and Medical System to provide intensive research, academic, and clinical care to nearly 2 million patients each year. The School of Medicine has nearly $600 million in extramural funding, with most of its academic departments ranking highly among all medical schools in the nation for research funding. As one of seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, trainees, residents and fellows. The combined medical school and medical system (“University of Maryland Medicine”) has an annual budget of more than $6 billion and an economic impact of nearly $20 billion on the state and local community. The School of Medicine, which ranks first 8th highest among public medical schools in research productivity (according to the Association of American Medical Colleges profile) is an innovator in translational medicine, with 606 active patents and 52 start-up companies. In the last US News and World Report ranking of best medical schools, released in 2021, UM School of Medicine is ranked #9 among the 92 public medical schools in the United States and in the richest 15% (#27) out of 192 public and private American medical schools. The School of Medicine works locally, nationally and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu