Background: Alterations in the ubiquitin-proteasome system (UPS) have been described in left ventricular hypertrophy and failure, although results have been inconsistent. The role of the UPS in right ventricular hypertrophy (RVH) and failure (RVF) is unknown. Given the greater percent increase in RV mass associated with RV afterload stress, as present in many congenital heart lesions, we hypothesized that alterations in the UPS could play an important role in RVH/RVF. Methods and Results: UPS expression and activity were measured in the RV from mice with RVH/RVF secondary to pulmonary artery constriction (PAC). Epoxomicin and MG132 were used to inhibit the proteasome, and overexpression of the 11S PA28α subunit was used to activate the proteasome. PAC mice developed RVH (109.3% increase in RV weight to body weight, RVW/BW), RV dilation with septal shift, RV dysfunction and clinical RVF. Proteasomal function (26S β5 chymotrypsin-like activity) was decreased 26% (p<0.05). Protein expression of 19S subunit Rpt5 (p<0.05), UCHL1 deubiquitinase (p<0.0001), and Smurf1 E3 ubiquitin ligase (p<0.01) were increased, as were polyubiquitinated proteins (p<0.05) and free-ubiquitins (p=0.05). Pro-apoptotic Bax was increased (p<0.0001), while anti-apoptotic Bcl-2 decreased (p<0.05) resulting in a 6-fold increase in Bax/Bcl-2 ratio. Proteasomal inhibition did not accelerate RVF. However, proteasome enhancement by cardiac-specific proteasome overexpression partially improved survival. Conclusions: Proteasome activity is decreased in RVH/RVF, associated with upregulation of key UPS regulators and pro-apoptotic signaling. Enhancement of proteasome function partially attenuates RVF suggesting that UPS dysfunction contributes to RVF.
- Right Ventricle
- Cardiac Hypertrophy
- Heart Failure
- Copyright © 2013, American Journal of Physiology - Heart and Circulatory Physiology