Improvement of cardiac contractile function by proteasome inhibition after pressure overload

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.