As our population ages, the number of people affected by heart failure continues to rise. A leading factor in the progression of this condition is the excessive buildup of fibrotic tissue in the heart, known as fibrosis. A research team from the Nagoya University Graduate School of Medicine in Japan has recently identified a crucial enzyme, protein kinase N (PKN), that plays a significant role in heart fibrosis. This enzyme triggers the transformation of heart fibroblasts into myofibroblasts, which compromises the structure of the heart and accelerates the decline in heart function.
The discovery, published in Nature Communications, revealed that removing this enzyme in preclinical models improved heart performance, suggesting that targeting PKN could be a powerful approach to treating heart failure.
Fibroblasts, small cells in the heart, work to maintain heart tissue. After injury, these cells often transform into myofibroblasts to aid in healing, creating connective tissues like collagen and elastin. However, in heart failure patients, myofibroblasts can go into overdrive, leading to an unhealthy buildup of tissue, a condition called fibrosis. This stiffens the heart muscle, reducing its ability to function properly and significantly increasing the risk of heart attacks.
The enzyme PKN has been linked to a signaling pathway responsible for activating heart fibroblasts. Drs. Satoya Yoshida, Mikito Takefuji, and Toyoaki Murohara from the Department of Cardiology at Nagoya University Graduate School of Medicine led the study. They suspected that PKN could be key to the harmful changes seen in heart fibrosis. Working alongside researchers at the Max Planck Institute, they set out to explore its role more deeply.
The team found that mammals have three forms of PKN: PKN1, PKN2, and PKN3. Using advanced RNA-sequencing techniques, they identified PKN1 and PKN2 as active in heart fibroblasts. In mouse models where PKN1 and PKN2 were deactivated, the researchers observed that while heart function remained stable, there was a significant reduction in the levels of actin and collagen—two essential proteins involved in fibrosis. Moreover, these mice showed no transformation of fibroblasts into myofibroblasts, suggesting a direct link between PKN activity and fibrosis.
According to Dr. Yoshida, “Although our research was conducted in mice, we have seen PKN expression in human heart fibroblasts as well, which gives us reason to believe similar outcomes may be achieved in human studies. Since nearly all heart diseases are tied to fibrosis, our findings have the potential to improve the outlook for many patients, particularly those with heart failure.”
Currently, no existing treatments specifically target PKN, but the research group is optimistic that their discovery will pave the way for the development of PKN inhibitors. These inhibitors could become a groundbreaking new treatment option for patients at high risk of heart failure.