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.

Inhibition of ubiquitin protein expression and 20S proteasome activity by irbesartan prevents post-infarction ventricular remodeling and decreases TNF-α generation

“…We also observed that irbesartan mainly inhibited the activity of UPS, indicating that irbesartan may exert a therapeutic effect on post-infarction ventricular remodeling, partly via the inhibition of ubiquitin expression and 20S proteasome activity. This finding was consistent with those of previous studies, which demonstrated that the inhibition of the proteasome resulted in the prevention of or decrease in pressure-induced hypertrophy in animals (6,28). UPS is an important quality control system for myocardial protein and an imbalance in this system may lead to HF (29).…”

“…Detailed knowledge regarding proteasome dynamics in cardiac disease phenotypes is essential for the development of therapeutic strategies (4). Previous studies demonstrated an effective reduction of LV hypertrophy via the inhibition of proteasome function and proteasome inhibitors were used to prevent or even induce a regression of LV hypertrophy in animal models (5,6).…”

Activation of the Bone Morphogenetic Protein Receptor by H11Kinase/Hsp22 Promotes Cardiac Cell Growth and Survival

“…Protein synthesis was measured by [ 3 H]phenylalanine incorporation. 14 Apoptosis was measured by caspase-3 activity 15 and by TUNEL staining, which was performed on sections treated with 2% H 2 O 2 to inactivate peroxidases and with 20 g/mL proteinase K for permeabilization. DNA fragments were labeled with 2 nmol/L biotinconjugated dUTP and 0.1 U/L deoxynucleotidyl transferase.…”

Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure

“…However, studies have been contradictory, showing either increased or decreased proteasomal enzyme activity in the afterload stressed LV (31, 43). Other models have demonstrated both cardioprotective (9, 21, 25, 59) and cardiotoxic (12,20,27,32,45,46) roles of the UPS via regulation of apoptosis, NF-B signaling, and oxidative stress.Although much is known about the molecular mechanisms of LVH and LV failure (LVF), the mechanisms underlying right ventricular (RV) hypertrophy (RVH) and RV failure (RVF) are less understood. RVH and RVF are a major cause of morbidity and mortality in patients with pulmonary hypertension and represent long-term risks for patients with surgically corrected congenital heart diseases such as tetralogy of Fallot, L-transposition of the great arteries, and hypoplastic left heart (4, 34).…”

“…However, studies have been contradictory, showing either increased or decreased proteasomal enzyme activity in the afterload stressed LV (31, 43). Other models have demonstrated both cardioprotective (9, 21, 25, 59) and cardiotoxic (12,20,27,32,45,46) roles of the UPS via regulation of apoptosis, NF-B signaling, and oxidative stress.…”