PKN Inhibition Reduces Cardiac Fibrosis and Improves Heart Function

The number of people suffering from heart failure is rising quickly as society ages. Heart failure progression is linked to fibrosis, or the overgrowth of fibrotic tissue in the heart. A team from the Graduate School of Medicine at Nagoya University in Japan has discovered the enzyme protein kinase N (PKN), which controls heart fibrosis.

The integrity of the heart is threatened by the enzyme's ability to catalyze the transformation of heart fibroblasts into myofibroblasts. Eliminating this enzyme resulted in a decrease in cardiac dysfunction, suggesting that anti-PKN therapies could be a viable treatment to shield patients from heart failure. The study was published in Nature Communications.

The heart makes use of tiny cells called fibroblasts to keep itself intact; these cells are frequently transformed into myofibroblasts following damage. By generating fibrous connective tissues like collagen and elastin, myofibroblasts facilitate the healing of wounds. Nevertheless, they frequently result in an excessive build-up of tissue in heart failure patients, which causes the heart tissue to stiffen and lose function—a condition known as fibrosis. A heart attack is more likely as a result of this process, which compromises the structural integrity of the heart.

Heart fibroblast activation has been linked to a signaling cascade involving the enzyme PKN. A team at the Department of Cardiology at the Nagoya University Graduate School of Medicine, under the direction of Drs. Satoya Yoshida, Mikito Takefuji, and Toyoaki Murohara, suspected that PKN was involved in the fibroblast-to-myofibroblast conversion observed in fibrosis. They looked into its function in cooperation with colleagues at the Max Planck Institute.

There are three types of PKN in mammalian cells: PKN1, 2, and 3. The researchers were able to identify PKN1 and 2 in heart fibroblasts by using RNA-sequencing data. Mice raised without PKN1 or PKN2 were used in the study. It was discovered that in the myocardial infarction and heart failure model, there was a significant decrease in actin and collagen expression, even though heart function remained unchanged.

These proteins play a crucial role in the accumulation of tissue seen in fibrosis. Additionally, they discovered that fibroblasts did not develop into myofibroblasts in mice with PKN1 and 2 suppression.

Although our study was done in a mouse model, PKN expression has been demonstrated in human heart fibroblasts, so similar results are expected in human trials.In fact, almost all heart diseases are closely related to heart fibrosis. I believe our findings contribute to improving the prognosis of many heart diseases, especially heart failure.”

Dr. Satoya Yoshida, Department of Cardiology, Graduate School of Medicine, Nagoya University

There are not any PKN-focused therapies available yet. Nevertheless, the team anticipates that PKN inhibitor development will result from the study. For those who are at risk of heart failure, such inhibitors would be a novel kind of treatment.