title: Proteasome inhibition decreases cardiac remodeling after initiation of pressure overload.
abstract: We tested the possibility that proteasome inhibition may reverse preexisting cardiac hypertrophy and improve remodeling upon pressure overload. Mice were submitted to aortic banding and followed up for 3 wk. The proteasome inhibitor epoxomicin (0.5 mg/kg) or the vehicle was injected daily, starting 2 wk after banding. At the end of the third week, vehicle-treated banded animals showed significant (P<0.05) increase in proteasome activity (PA), left ventricle-to-tibial length ratio (LV/TL), myocyte cross-sectional area (MCA), and myocyte apoptosis compared with sham-operated animals and developed signs of heart failure, including increased lung weight-to-TL ratio and decreased ejection fraction. When compared with that group, banded mice treated with epoxomicin showed no increase in PA, a lower LV/TL and MCA, reduced apoptosis, stabilized ejection fraction, and no signs of heart failure. Because overload-mediated cardiac remodeling largely depends on the activation of the proteasome-regulated transcription factor NF-kappaB, we tested whether epoxomicin would prevent this activation. NF-kappaB activity increased significantly upon overload, which was suppressed by epoxomicin. The expression of NF-kappaB-dependent transcripts, encoding collagen types I and III and the matrix metalloprotease-2, increased (P<0.05) after banding, which was abolished by epoxomicin. The accumulation of collagen after overload, as measured by histology, was 75% lower (P<0.05) with epoxomicin compared with vehicle. Myocyte apoptosis increased by fourfold in hearts submitted to aortic banding compared with sham-operated hearts, which was reduced by half upon epoxomicin treatment. Therefore, we propose that proteasome inhibition after the onset of pressure overload rescues ventricular remodeling by stabilizing cardiac function, suppressing further progression of hypertrophy, repressing collagen accumulation, and reducing myocyte apoptosis.
authors.affiliation: Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Hedhli
authors.forename: Paulo
authors.initials: P
authors.lastname: Lizano
authors.forename: Chull
authors.initials: C
authors.lastname: Hong
authors.forename: Luke F
authors.initials: LF
authors.lastname: Fritzky
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Dhar
authors.forename: Huasheng
authors.initials: H
authors.lastname: Liu
authors.forename: Yimin
authors.initials: Y
authors.lastname: Tian
authors.forename: Shumin
authors.initials: S
authors.lastname: Gao
authors.forename: Kiran
authors.initials: K
authors.lastname: Madura
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.forename: Christophe
authors.initials: C
authors.lastname: Depre
mesh_terms: D000818:Animals; D001011:Aorta / Q000601:surgery; D017209:Apoptosis / Q000187:drug effects; D001794:Blood Pressure; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D008026:Ligation; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D016328:NF-kappa B; D009842:Oligopeptides; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin