Proteasome inhibition in experimental right ventricular hypertrophy

Más información sobre el libro

Right ventricular hypertrophy (RVH) due to pulmonary hypertension (PH) leads to maladaptive cardiac remodeling and is a major cause of death in PH patients. As RVH is a key prognostic factor, alleviating it is crucial for future therapies. The 26S proteasome, a large protease responsible for degrading over 80% of cellular proteins, is activated in various cardiomyopathies and rodent models of left ventricular hypertrophy (LVH). In LVH, partial proteasome inhibition has been shown to suppress and even reverse the condition, indicating that enhancing proteasome function may contribute to cardiac hypertrophy and serves as a potential therapeutic target. In this study, RVH was induced in mice through pulmonary artery banding (PAB), and the expression and activity of the proteasome were analyzed in hypertrophied right ventricles compared to sham-operated controls. Significant RVH developed in all mice three weeks post-PAB, with increased proteasome expression and activity noted in hypertrophied hearts, particularly the formation of 26S proteasome and the regulatory subunit Rpn6. Two proteasome inhibitors, Bortezomib and ONX-0912, were tested for their preventive and therapeutic effects. Preventive treatment partially improved RVH, while therapeutic administration after hypertrophy development led to improved RV structure and function, with ONX showing greater efficacy than Bortezomib. This study suggests that proteasome inhibition