Primary proteasome inhibition results in cardiac dysfunction

Area of Science:

• Cardiovascular Physiology
• Molecular Biology
• Proteasome Function

Background:

• The proteasome is crucial for intracellular protein degradation.
• Proteasome impairment can cause cellular and tissue dysfunction.
• Previous studies linked proteasome dysfunction to coronary vascular alterations.

Purpose of the Study:

• To investigate the effects of chronic proteasome inhibition (PSI) on cardiac structure and function.
• To test the hypothesis that PSI induces detrimental changes in the heart.
• To utilize a previously established animal model for cardiovascular research.

Main Methods:

• Domestic pigs received twice-weekly subcutaneous injections of the proteasome inhibitor MLN-273 or a control.
• Cardiac structure, function, myocardial perfusion, and microvascular permeability were assessed using electron beam computed tomography after 11 weeks.
• Ex vivo analyses included immunoblotting, immunostaining, TUNEL, Masson trichrome, and Congo red staining to evaluate cellular changes.

Main Results:

• Proteasome inhibition led to increased left ventricular (LV) mass and altered diastolic filling.
• Cardiac output was significantly reduced, and ejection fraction tended to decrease in the PSI group.
• Tissue analysis revealed proteasome substrate accumulation, apoptosis, fibrosis, reduced myocardial perfusion, and increased microvascular permeability.

Conclusions:

• Chronic proteasome inhibition induces significant structural and functional alterations in the heart.
• The observed cardiac changes are consistent with a hypertrophic-restrictive cardiomyopathy phenotype.
• These findings underscore the proteasome's critical role in maintaining cardiovascular health.