Protein Kinase N (PKN) to Fight Heart Failure, A New Approach

Heart failure is one of the leading causes of death worldwide, affecting millions of people. While we often think of heart failure as a problem with heart muscles, new research reveals that the issue runs deeper than that. A recent study published in Nature Communications focuses on a protein called Protein Kinase N (PKN) and its significant role in heart failure. The findings of this study shed light on how this protein contributes to a process called cardiac fibrosis, which is the buildup of scar tissue in the heart, leading to its stiffness and reduced ability to function properly.

Mikito Takefuji, co-author, highlights the potential clinical implications:
“Targeting PKN could be a safer and more specific approach to managing heart failure, especially compared to existing therapies that affect broader biological processes and carry unwanted side effects.”

Cardiac fibrosis happens when the heart experiences stress, often due to events like a heart attack. When heart muscle cells, known as cardiomyocytes, die, the heart has to respond by creating new tissue to maintain its structure. Unfortunately, the tissue that forms is not as functional as the original heart muscle. Instead, it becomes fibrotic, meaning it is stiff and not capable of contracting and pumping blood as efficiently. This process is critical in preventing the heart from collapsing, but, over time, the excess scar tissue becomes harmful, leading to heart failure.

The researchers in this study focused on a key player in this process: cardiac fibroblasts, which are cells in the heart responsible for producing the building blocks of this scar tissue. Normally, fibroblasts are inactive, but when the heart is under stress, these cells change into a more active form called myofibroblasts. In this state, they start producing large amounts of extracellular matrix (ECM), the substance that makes up scar tissue. The transformation of fibroblasts into myofibroblasts is at the heart of fibrosis.

Satoya Yoshida, lead author, explains the significance of their findings:
“We discovered that Protein Kinase N plays a critical role in transforming fibroblasts into scar-forming myofibroblasts. By blocking this process, we were able to reduce heart fibrosis, which opens new doors for treating heart failure.”

The study’s breakthrough finding is that PKN is a key protein that drives this change. PKN acts like a switch, turning on the fibroblasts and pushing them to become myofibroblasts. It does this through a chain reaction involving another protein called p38. When PKN activates p38, the fibroblasts begin producing too much ECM, which leads to the harmful buildup of fibrotic tissue. This is a crucial insight because it shows how targeting PKN could potentially stop or slow down the process of fibrosis, providing a new way to treat heart failure.

In experiments, the researchers created genetically modified mice that lacked the PKN gene specifically in their fibroblasts. These mice had far less fibrosis and better heart function compared to normal mice. In models of heart failure, where mice experienced heart attacks or had conditions similar to human heart failure with preserved ejection fraction (HFpEF), the mice without PKN showed less scar tissue and their hearts worked better. This suggests that turning off PKN could be a powerful way to prevent the heart from becoming too stiff and fibrotic after a heart attack or in chronic heart failure.

One of the most promising parts of this discovery is that while targeting PKN reduces fibrosis, it doesn’t seem to interfere with other important processes. For example, many treatments that block the action of TGF-β, another protein involved in fibrosis, have serious side effects because TGF-β is also important for immune regulation. Blocking TGF-β can sometimes lead to immune system problems, but targeting PKN appears to be much more specific to the fibrosis process without affecting other vital functions. This makes it a much safer potential treatment option.

Another key takeaway from this research is its relevance to a particular type of heart failure known as HFpEF. This condition is becoming increasingly common, especially in older adults, and is characterized by the heart’s inability to relax properly between beats, leading to poor blood flow. Fibrosis is a major cause of this stiffness. Studies have shown that patients with HFpEF often have very stiff hearts due to extensive fibrotic tissue. The findings from this study indicate that by reducing PKN activity, it might be possible to ease the stiffness and improve heart function in HFpEF patients.

Tatsuya Yoshida, another key researcher, adds:
“Our results show that reducing PKN activity in heart fibroblasts significantly improved heart function in our models, pointing to a promising new therapeutic target for preventing or reversing heart damage.

The discovery of PKN’s role in fibrosis opens up exciting possibilities for future treatments. Current therapies for heart failure focus mostly on managing symptoms, like controlling blood pressure and reducing the strain on the heart. However, there are very few treatments that directly address the underlying causes of fibrosis. By targeting PKN, researchers may be able to slow down or even reverse the progression of heart failure by reducing the buildup of scar tissue.