How RNA Editing Could Offer New Insights Into Heart Disease

November 16, 2024 – by Rebecca Handler

When you think of heart disease, you might picture clogged arteries caused by unhealthy eating or lack of exercise. But what if there’s more to the story – something hidden in our genetic code? Chad Weldy, MD, PhD, a cardiologist and researcher at Stanford Department of Medicine, is investigating how RNA editing – i.e. the fine tuning of genetic instructions at the cellular level – plays a critical role in heart health. His research could transform how we understand and treat coronary artery disease.

What Is RNA Editing, and How Does It Differ From DNA Mutations?

DNA, often called the blueprint of life, contains the instructions for making proteins. RNA acts as a messenger, carrying these instructions to the cell’s protein-making machinery. While DNA mutations are permanent changes that can be passed down through generations, changes made through RNA editing are temporary. In the process of RNA editing, special proteins, called ADARs, make small changes to the RNA message without altering the DNA itself. This allows cells to quickly adjust and fine-tune protein production in response to changes or stress.

In other terms, think of RNA editing as tweaking a recipe by swapping out one ingredient. ADAR proteins can change one RNA building block into another, altering how proteins are made or even stopping certain messages from triggering the body’s immune system.

Connecting RNA Editing to Coronary Artery Disease

Weldy's work focuses on a specific protein, called ADAR1, which edits RNA to prevent the immune system from mistaking the body’s own cells for invading viruses. “Our cells are constantly on alert, scanning for threats like viruses that use double-stranded RNA as part of their genetic material,” he explained. “ADAR1 helps by making sure our cells don’t confuse our own RNA for an enemy.”

If ADAR1 doesn’t work properly, the body’s defense system can mistake normal RNA for a virus, leading to inflammation. This reaction can even cause cells to shut down. In heart disease, this immune response may lead to chronic inflammation in the arteries, contributing to plaque buildup.

Weldy’s research, within the lab of Thomas Quertermous, MD, the William G. Irwin Professor of Cardiovascular Medicine, discovered that when RNA editing is impaired in artery cells, the body’s defenses are triggered unnecessarily, speeding up the formation of plaques that can block blood flow. His work builds upon foundational research by his collaborator, Jin Billy Li, PhD, professor of genetics at Stanford. 

"Back In 2015, my lab and collaborators discovered that RNA editing by ADAR1 is crucial," explained Li. "If long strands of double-stranded RNA (dsRNA) aren’t edited by ADAR1, the body mistakes them for viruses, which triggers an immune response.” Li and his team found that when this editing doesn’t happen, it can lead to inflammation seen in common diseases like coronary artery disease.

Challenging Traditional Views on Heart Disease

Traditional explanations for plaque buildup in the arteries (known as atherosclerosis), focus on factors like cholesterol levels, diet, and physical activity. But building on Li’s findings, Weldy’s research suggests a genetic component tied to how well cells perform their job of RNA editing. This new understanding could explain why some people suffer heart attacks even when they have no apparent risk factors. It may also clarify why there’s often a “residual risk” of heart disease, even in patients with excellent cholesterol control.

To explore new treatment possibilities, Weldy is investigating the connection between the body’s immune response and RNA editing. A key player in this process is a sensor in our cells called MDA5, that typically detects viral threats. However, when ADAR1 RNA editing is inadequate, MDA5 becomes overly active and drives the progression of atherosclerosis.

“We’re exploring ways to block MDA5 or enhance RNA editing as a treatment strategy,” he shared. Such targeted approaches could benefit patients whose heart disease is influenced more by genetic factors than lifestyle choices.

As Quertermous explains, “If we can create a therapy to reduce MDA5 activity, we could develop an 'editing risk score' that measures the number of harmful RNA changes in each person.” This score would help identify high-risk patients, who could then receive targeted treatment as part of a personalized approach that also considers other genetic and traditional risk factors.

The Broader Implications of RNA Editing

Beyond heart disease, impaired RNA editing may be linked to other autoimmune conditions like lupus, rheumatoid arthritis, and type 1 diabetes. Weldy is excited about expanding his research to explore these connections further. “This pathway of RNA editing and immune response is likely a common thread in several diseases,” he explained. As RNA editing therapies gain momentum, there is hope that precision medicine—tailoring treatments to an individual’s genetic profile—is within reach.

“Precision medicine has mostly focused on rare diseases because their underlying causes may be easier to understand,” explains Li. “However, our work on RNA editing connects these genetic mechanisms to more common diseases. This approach helps us identify the genetic risks in individual patients, bringing precision medicine closer to treating conditions like autoinflammatory diseases.”

Weldy's work was recently recognized as a finalist for a prominent national award from the American Heart Association, the Louis N. and Arnold M. Katz Basic Science Research Prize. He will present his findings at the AHA Scientific Sessions meeting on November 16th, 2024 in Chicago.

Ultimately, this research offers a promising glimpse into the future of cardiovascular care. By understanding how our cells edit RNA and how these processes can go wrong, researchers may soon have new tools to detect and treat heart disease more effectively. As science continues to uncover the complexities of RNA, what we know about genetic risk and heart health might just be the beginning.