NEDD4-Mediated GSNOR Degradation Aggravates Cardiac Hypertrophy and Dysfunction.

Summary

This preclinical study shows that NEDD4 ubiquitinates and degrades GSNOR, driving pressure-overload cardiac hypertrophy. Genetic NEDD4 ablation or pharmacologic inhibition (including indole-3-carbinol) restored GSNOR, blunted hypertrophy, and improved function, highlighting a druggable pathway.

Key Findings

• GSNOR protein is reduced without mRNA change in hypertrophic human and TAC mouse myocardium, implicating post-translational regulation.
• NEDD4 acts as the E3 ubiquitin ligase for GSNOR, increasing its ubiquitination and degradation in hypertrophic hearts.
• Cardiomyocyte-specific NEDD4 deficiency or pharmacological NEDD4 inhibition suppresses GSNOR ubiquitination, reduces hypertrophy, and improves cardiac function.
• Indole-3-carbinol (a clinical NEDD4 inhibitor) demonstrated efficacy comparable to a selective NEDD4 inhibitor in mitigating hypertrophy.

Clinical Implications

While preclinical, targeting NEDD4-GSNOR could complement current neurohormonal therapies by directly modulating pathological remodeling. It suggests biomarker-driven trials of NEDD4 inhibition in hypertrophy/heart failure.

Limitations

• Preclinical models; no human interventional data to confirm efficacy and safety of NEDD4 inhibitors in heart failure.
• Potential off-target effects and pleiotropy of NEDD4 and indole-3-carbinol require careful evaluation.

Future Directions

Biomarker-guided early-phase trials of NEDD4 inhibition in hypertrophy/heart failure; exploration of combination therapy with guideline-directed agents; refinement of cardiac-selective NEDD4 modulators.