Proteasome inhibition decreases cardiac remodeling after initiation of pressure overload

Document Type

Article

Publication Date

10-1-2008

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-κB, we tested whether epoxomicin would prevent this activation. NF-κB activity increased significantly upon overload, which was suppressed by epoxomicin. The expression of NF-κB-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. Copyright © 2008 the American Physiological Society.

Identifier

57049121279 (Scopus)

Publication Title

American Journal of Physiology Heart and Circulatory Physiology

External Full Text Location

https://doi.org/10.1152/ajpheart.00532.2008

e-ISSN

15221539

ISSN

03636135

PubMed ID

18676687

First Page

H1385

Last Page

H1393

Issue

4

Volume

295

Grant

R01AG014121

Fund Ref

National Institute on Aging

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