A team of researchers at Seoul National University Hospital (SNUH) has identified the mechanism that causes dilated cardiomyopathy (DCM), a heart disease in which the muscles of the left ventricle (one of the four chambers of the heart), the heart's core chamber that pumps fresh blood from the lungs to the outside of the heart, become stretched. The hospital said this was the world's first.
Dilated cardiomyopathy is a typical disease that causes heart failure. Currently, there are only supportive drug treatments and no fundamental treatment to induce cardiomyocyte regeneration.
SNUH said Wednesday that the team -- Professor Kim Hyo-soo of the Biomedical Research Institute, Professor Cho Hyun-jai of the Department of Cardiology, and researcher Kang Min-joon of the Cardiovascular Research Center -- created a cardiomyocyte-specific latrophilin-2 defective mouse model induced by tamoxifen and analyzed its characteristics, identifying for the first time a new pathological mechanism by which latrophilin-2 defects cause dilated cardiomyopathy.
The team was the first to show five years ago that latrophilin-2 is selectively expressed in cardiomyocyte stem cells and that its deletion leads to embryonic lethality by preventing the heart from developing normally. This demonstrates that the gene is essential for life.
The recent study summarizes the results of a two-year study in which a genetically engineered mouse model was created and characterized over two years to determine the role of latrophilin-2 in the adult heart.
The researchers found that latropilin-2 plays a key role in regulating mitochondrial function and intercellular junctions in the myocardium, and that its deficiency leads to poor cardiac function and heart failure.
Mice treated with tamoxifen to remove latropilin-2 from cardiomyocytes died suddenly within a few days. In a model of myocardial infarction, mortality was found to be significantly higher than in controls. Electrocardiogram monitoring suggested that arrhythmias and atrioventricular conduction block were the cause of death.
In addition, gross anatomical examination revealed a greatly dilated heart, histological examination showed disorganized and disconnected myocardial fibers, and electron microscopic examination showed disorganized myocardial fibers and disrupted mitochondria. Mitochondrial function was analyzed by dissolving the heart and isolating cardiomyocytes, which revealed a decreased mitochondrial membrane potential and reactive oxygen species (ROS) accumulation.
Analysis of the mechanisms of this phenomenon revealed that loss of latrophilin-2 decreases the activity of the p38-MAPK pathway, which in turn decreases the expression of cardiomyocyte intercellular adhesion factors (Adherens, Desmosome, Connexin), leading to the disassembly of myocardial fibers, and simultaneously decreases the expression of the mitochondrial regulatory protein PGC-1α, resulting in a decrease in the amount and structure of mitochondria and a decline in the efficiency of energy production and impaired cardiac function.
To demonstrate this pathophysiology, the team found that treatment with a p38-MAPK pathway activator rescued dilated cardiomyopathy in latropilin-2 knockout mice. This demonstrated that heart failure caused by latrophilin-2 deficiency can be improved, which is expected to be an important basis for developing future heart failure therapies.
“The heart needs to keep beating continuously, so the function of mitochondria and the physical coupling between cardiomyocytes are crucial,” Professor Kim said. “Our study demonstrates that when latropilin-2 is missing in cardiomyocytes, these functions and structures are impaired, leading to heart failure and sudden death.”
Kim continued, “Because latrophilin-2 has an almost identical gene sequence in mice and humans, our findings may also apply to humans. As a therapeutic agent, we are developing a latrophilin-2 gene therapy, a ligand that can stimulate the cell surface receptor called latrophilin-2.”