Study sheds new light on the role of the NSUN2 protein in cardiac hypertrophy and heart failure

Study sheds new light on the role of the NSUN2 protein in cardiac hypertrophy and heart failure

A recent study published inMechanical engineeringhas shed new light on the role of the protein NSUN2 in the development of cardiac hypertrophy and heart failure. Research conducted by a team at Harbin Medical University shows that NSUN2, a member of the NOL1/NOP2/Sun domain family, significantly contributes to pathological cardiac hypertrophy through activation of the LARP1-GATA4 axis and may provide a new therapeutic target for heart failure.

The study began with the observation that NSUN2 expression levels were significantly increased in both human hearts with heart failure (HF) and mouse hearts subjected to hypertrophy induced by transverse aortic constriction (TAC) and angiotensin II (Ang II) treatment. This finding prompted researchers to investigate the specific function of NSUN2 in cardiac hypertrophy and heart failure. Through a series of experiments using cardiomyocyte-specific knockout and overexpression of NSUN2, the team discovered that NSUN2 plays a critical role in regulating heart function and structure.

In their experiments, the researchers found that cardiomyocyte-specific knockout of NSUN2 attenuated the reduced cardiac ejection fraction (EF) and fractional shortening (FS) observed in TAC-treated mice, while simultaneously reducing the heart weight to tibia length (HW/TL) ratio. Conversely, cardiac-specific overexpression of NSUN2 resulted in pronounced cardiac remodeling characterized by increased hypertrophic growth, cardiac fibrosis, and a significant decrease in EF and FS. These results highlight the deleterious effects of NSUN2 overexpression on cardiac function and structure.

Mechanistically, the study revealed that NSUN2 induces 5-methylcytosine (m5C) modification of La-related protein 1 (LARP1), thereby increasing its mRNA stability. This process is mediated by the Y-box binding protein 1 (YBX1). The stabilized LARP1 then interacts with GATA binding protein 4 (GATA4) mRNA, prevents their degradation and ultimately promotes a pro-hypertrophic phenotype. To validate this pathway, the researchers performed RNA immunoprecipitation (RIP) assays and found that LARP1 binds directly toGATA4mRNA, which protects them from degradation.

To further support this mechanism, the researchers demonstrated silencingLARP1partially attenuated TAC-induced cardiac hypertrophy and heart failure. Similarly, mice with NSUN2 overexpression experienced degradationLARP1significantly reduced the hypertrophic response, as evidenced by decreased expression of hypertrophic markers such as ANP and BNP. These results highlight the importance of the NSUN2/LARP1/GATA4 axis in mediating cardiac hypertrophy.

The study also examined the broader impact of NSUN2 regulation on heart health. By analyzing RNA sequencing data, researchers identified numerous genes with altered expression in response to NSUN2 activity, many of which are involved in signaling pathways associated with cardiac hypertrophy and heart failure. This comprehensive analysis provides a deeper understanding of the molecular mechanisms underlying the effects of NSUN2 on cardiac function.

The study published inMechanical engineeringprovides valuable insights into the role of NSUN2 in cardiac hypertrophy and heart failure. By elucidating the NSUN2/LARP1/GATA4 axis, the study not only expands our understanding of the molecular basis of these diseases but also highlights NSUN2 as a potential therapeutic target for the prevention and treatment of heart failure. Future research could focus on exploring the therapeutic potential of targeting NSUN2 and its downstream signaling pathways to mitigate cardiac hypertrophy and improve cardiac function.

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