title: Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure.
abstract: 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 (RV) hypertrophy (RVH) and RV 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. 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), 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), whereas anti-apoptotic Bcl-2 decreased (P < 0.05), resulting in a sixfold increase in the Bax/Bcl-2 ratio. Proteasomal inhibition did not accelerate RVF. However, proteasome enhancement by cardiac-specific proteasome overexpression partially improved survival. 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.
authors.affiliation: Department of Pediatrics (Cardiology Stanford University School of Medicine, Stanford, California;
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Rajagopalan
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.forename: Sushma
authors.initials: S
authors.lastname: Reddy
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fajardo
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.forename: Shannamar
authors.initials: S
authors.lastname: Dewey
authors.forename: Aldrin V
authors.initials: AV
authors.lastname: Gomes
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003250:Constriction; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006333:Heart Failure / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D006439:Hemodynamics / Q000187:drug effects; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000503:physiopathology / Q000601:surgery; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism*; D018497:Ventricular Dysfunction, Right / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D016278:Ventricular Function, Right / Q000187:drug effects
chemical_list: D061988:Proteasome Inhibitors; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: cardiac hypertrophy; heart failure; proteasome; right ventricle; ubiquitin