NEDD4-Mediated GSNOR Degradation Aggravates Cardiac Hypertrophy and Dysfunction

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Biochemistry

Background:

• Decreased S-nitrosoglutathione reductase (GSNOR) exacerbates cardiomyopathy by increasing S-nitrosylation under hemodynamic stress.
• Mechanisms underlying GSNOR decrease in cardiac hypertrophy remain largely unknown.
• Identifying novel regulators of GSNOR is crucial for understanding and treating cardiac hypertrophy.

Purpose of the Study:

• To identify novel molecules involved in the pathogenesis of pressure overload-induced cardiac hypertrophy.
• To elucidate the role of NEDD4 (neuronal precursor cell expressed developmentally downregulated 4) in regulating GSNOR levels.
• To evaluate the therapeutic potential of targeting the NEDD4/GSNOR axis in cardiac hypertrophy.

Main Methods:

• Utilized protein synthesis and degradation inhibitors to investigate GSNOR regulation.
• Employed mass spectrometry to identify NEDD4, an E3 ubiquitin ligase, as a key player in GSNOR decrease.
• Generated cardiomyocyte-specific NEDD4-deficient mice and used NEDD4 inhibitors (IBM and indole-3-carbinol) to assess in vivo and in vitro effects on cardiac hypertrophy.

Main Results:

• GSNOR protein levels were reduced in hypertrophic myocardium, while mRNA remained stable, suggesting post-translational regulation.
• NEDD4 expression was elevated in hypertrophic samples and directly associated with GSNOR ubiquitination.
• NEDD4 deficiency or inhibition significantly reduced GSNOR ubiquitination and ameliorated cardiac hypertrophy in vitro and in vivo.

Conclusions:

• Upregulated NEDD4 promotes cardiac hypertrophy by inducing GSNOR ubiquitination and degradation.
• Targeting NEDD4 with specific inhibitors represents a promising therapeutic strategy for cardiac hypertrophy and heart failure.
• The NEDD4/GSNOR pathway is a critical determinant in the progression of cardiac hypertrophy.