Scientists discovered that a protein called TBK1 plays a major role in causing heart disease by triggering changes in blood vessel cells. When they reduced TBK1 in mice, it prevented plaque buildup in arteries—the main cause of heart attacks and strokes. Even more exciting, a new drug called GSK8612 that blocks TBK1 showed promise in stopping this process without needing to lower cholesterol. This research suggests that targeting TBK1 could become a powerful new way to treat heart disease, offering hope for millions of people worldwide.

The Quick Take

  • What they studied: How a protein called TBK1 causes plaque to build up in arteries and whether blocking it could prevent heart disease
  • Who participated: Laboratory mice genetically designed to develop heart disease, plus human blood vessel cells grown in dishes
  • Key finding: Mice without TBK1 in their blood vessels developed significantly less plaque buildup, and a drug that blocks TBK1 reduced plaque formation without changing cholesterol levels
  • What it means for you: This suggests a new type of heart disease medicine might be developed that works differently than current cholesterol drugs, potentially helping people who don’t respond well to existing treatments. However, this is early research and human testing is still needed.

The Research Details

Researchers used multiple advanced techniques to study how TBK1 works. First, they examined blood vessel tissue from mice and humans with heart disease to see if TBK1 was more active. They then created special mice that lacked TBK1 specifically in their blood vessel cells and fed them a diet that normally causes heart disease. They tracked whether these mice developed less plaque than normal mice. Finally, they tested a new drug called GSK8612 that blocks TBK1 to see if it could prevent plaque buildup.

The team used cutting-edge molecular tools to understand exactly how TBK1 causes problems. They identified which other proteins TBK1 interacts with and how these interactions trigger the harmful changes in blood vessel cells. This detective work revealed a specific chain reaction that leads to plaque formation.

This approach is powerful because it combines observations from real human tissue, controlled experiments in mice, and detailed molecular analysis. This multi-layered approach helps ensure the findings are reliable and relevant to actual human disease.

Understanding the exact mechanism of how TBK1 causes heart disease is crucial because it reveals a new target for treatment. Previous research showed that cholesterol-lowering drugs don’t prevent all heart disease, meaning other processes are involved. By identifying TBK1’s role, scientists can develop drugs that attack the problem from a different angle, potentially helping more people.

This research was published in Circulation Research, a highly respected journal in cardiovascular science. The study used multiple complementary techniques (genetic manipulation, drug testing, molecular analysis) which strengthens confidence in the findings. The results were consistent across both mouse models and human cell studies. However, the research was conducted in laboratory settings and mice, so human clinical trials are still needed to confirm these results work in actual patients.

What the Results Show

The researchers found that TBK1 protein is significantly more active in blood vessels affected by heart disease compared to healthy blood vessels. When they removed TBK1 from the blood vessel cells of mice prone to heart disease, these mice developed much less plaque buildup in their arteries compared to normal mice—even when eating the same unhealthy diet.

When they tested the drug GSK8612, which blocks TBK1, it produced similar protective effects. Mice treated with this drug developed fewer atherosclerotic plaques (the fatty deposits that clog arteries). Importantly, the drug worked without lowering cholesterol levels, suggesting it fights heart disease through a completely different mechanism than current medications.

The molecular analysis revealed how TBK1 causes damage: it activates a chain reaction involving proteins called PAK1 and ERK1/2. This chain reaction triggers a harmful transformation of blood vessel cells, turning them into cells that promote plaque formation. By blocking TBK1, this entire harmful chain reaction is stopped.

Both male and female mice showed protection from TBK1 reduction, suggesting this approach could work equally well for men and women.

The research showed that inflammatory molecules (TNF-α and IL-1β), which are elevated in people with heart disease, trigger TBK1 activation. This suggests that TBK1 is a key link between inflammation and plaque formation. The study also demonstrated that blocking TBK1 reduced the transformation of blood vessel cells into plaque-promoting cells, which is a critical step in heart disease development.

Previous research identified that TBK1 gene mutations are more common in heart disease patients, but scientists didn’t understand why. This study explains the mechanism and shows that TBK1 is not just associated with heart disease—it actively causes it. Unlike cholesterol-lowering drugs that reduce one risk factor, this approach targets the underlying inflammatory process that drives plaque formation, representing a novel therapeutic strategy.

This research was conducted in mice and laboratory cell cultures, not in living humans. While mice are useful for understanding disease mechanisms, they don’t always respond the same way humans do. The study used genetically modified mice designed to develop heart disease, which may not perfectly mirror how the disease develops in humans. Additionally, the long-term safety and effectiveness of TBK1 inhibitors in humans remains unknown. The drug GSK8612 is still experimental and has not been tested in human patients. Finally, the study didn’t examine how TBK1 inhibition might interact with other heart disease medications that people currently take.

The Bottom Line

Based on this research, TBK1 inhibitors appear to be a promising new approach for treating heart disease (moderate confidence level). However, these drugs are still in early development and are not yet available for patients. People with heart disease should continue taking their current medications as prescribed by their doctors. This research suggests that in the future, TBK1-blocking drugs might be added to treatment plans, potentially helping people who don’t respond well to cholesterol medications alone.

This research is most relevant to people with heart disease or at high risk for it, particularly those who don’t achieve adequate protection with current cholesterol-lowering medications. It’s also important for cardiologists and researchers developing new heart disease treatments. People with normal heart health don’t need to take action based on this research yet, as the drugs are not available and human testing hasn’t begun.

If TBK1 inhibitors move forward to human testing, it typically takes 5-10 years for a new drug to be approved for patient use. Even then, benefits would likely be seen over months to years of treatment, similar to how current heart disease medications work. This is not a quick fix but rather a long-term preventive approach.

Want to Apply This Research?

  • Once TBK1 inhibitors become available, users could track inflammatory markers (like high-sensitivity C-reactive protein) through periodic blood tests, along with traditional heart disease risk factors like blood pressure, cholesterol levels, and weight. The app could help users log these measurements and visualize trends over time.
  • While waiting for new medications, users can reduce TBK1 activation by managing inflammation through lifestyle changes: regular exercise, anti-inflammatory diet (Mediterranean diet), stress reduction, adequate sleep, and smoking cessation. The app could help track these behaviors and their correlation with heart health markers.
  • Users should establish a baseline of their cardiovascular risk factors and inflammatory markers, then monitor these quarterly or semi-annually. The app could send reminders for blood work appointments and help users discuss results with their doctors. Once TBK1 inhibitors become available, the app could track medication adherence and any changes in symptoms or test results.

This research describes early-stage laboratory and animal studies of a potential new heart disease treatment. TBK1 inhibitors are not yet approved for human use and have not been tested in patients. This information is for educational purposes only and should not be used to make medical decisions. Anyone with heart disease or at risk for it should continue following their doctor’s current treatment plan and discuss any new research with their healthcare provider before making changes. Do not stop or modify any heart disease medications without consulting your physician.