A new study from Harbin Medical University, published in the journal Engineering, has identified a key role for the protein NSUN2 in the development of cardiac hypertrophy and heart failure. The research indicates that NSUN2 contributes to pathological cardiac hypertrophy by activating the LARP1-GATA4 axis, suggesting it could be a novel target for heart failure therapies.
Researchers observed that NSUN2 levels were higher in both human hearts with heart failure and in mouse models where hypertrophy was induced. This prompted further investigation into how NSUN2 affects heart structure and function. Using genetically modified mice, the team found that removing NSUN2 specifically from heart muscle cells improved cardiac function after stress, while overexpressing it led to increased heart enlargement, fibrosis, and reduced cardiac performance.
The study detailed how NSUN2 modifies La-related protein 1 (LARP1) through a chemical process called m5C methylation, which increases LARP1’s stability. Y-box binding protein 1 (YBX1) mediates this effect. Stabilized LARP1 then binds to GATA4 mRNA, protecting it from degradation and promoting growth responses associated with hypertrophy.
Additional experiments showed that reducing LARP1 levels lessened the negative effects of stress on the heart in mice. Similarly, knocking down LARP1 in mice with high levels of NSUN2 reduced markers of hypertrophy. These findings point to the importance of the NSUN2/LARP1/GATA4 pathway in driving harmful changes in the heart.
Through RNA sequencing analysis, researchers also identified many genes affected by changes in NSUN2 activity. Many of these genes are linked to pathways involved in cardiac hypertrophy and failure.
The authors conclude that understanding this pathway provides important insights into molecular mechanisms behind heart disease and identifies possible directions for future treatments targeting NSUN2 or its downstream partners.
