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Improvement of cardiac contractile function by proteasome inhibition after pressure overload
Author(s) -
Hedhli Nadia,
Liu Huasheng,
Madura Kiran,
Hong Chull,
Vatner Stephen F,
Depre Christophe
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.970.9
Subject(s) - ventricle , muscle hypertrophy , medicine , endocrinology , pressure overload , chemistry , heart failure , cardiac function curve , cardiac hypertrophy
The goal of this study was to determine if proteasome inhibition (PI) could regress pre‐existing hypertrophy and collagen accumulation. Mice were submitted to transverse aortic banding (B) for 3 weeks and compared to shams (S). Two weeks after B, mice were treated daily with the proteasome inhibitor epoxomicin (E, 0.5 mg/kg) or with the vehicle (V). After 3 weeks B, B‐V showed an increase in proteasome activity (PA: 347±19in B‐V vs.114±7 in S, P<0.05), and left ventricle/tibial length (LV/TL: 10.2±0.56 in B‐V vs.6.2±0.3 in S, P<0.05). B‐V mice developed signs of heart failure shown by a decreased ejection fraction (EF: 50±4 in B‐V vs. 75±2 in S P<0.05). Compared to the B‐V, B‐E mice showed significantly lower PA (85±5, p<0.05 vs. B‐V) and LV/TL (8.4±0.3, P<0.05 vs. B‐V), and a better EF (62±4, P<0.05 vs. B‐V). Because pressure overload activates the expression of collagen and matrix metalloproteases (MMP), we tested whether E would prevent this activation. Transcripts of collagen type 1 and MMP2 increased 4‐fold in B‐V versus sham (P<0.05), which was abolished in B‐E. As a result, accumulation of interstitial collagen after B was lower in B‐E versus B‐V (1.6±0.8 in B‐E vs. 9.0±0.5 in B‐V, P<0.05). Therefore, PI started after B rescues ventricular function and decreases myocyte hypertrophy and collagen accumulation.