Proteasome inhibition slightly improves cardiac function in mice with hypertrophic cardiomyopathy.

Saskia Schlossarek,Sonia R Singh,Birgit Geertz,Lucie Carrier,Silke Reischmann,Herbert Schulz,Norbert Hã¼Bner

doi:10.3389/fphys.2014.00484

Abstract

A growing line of evidence indicates a dysfunctional ubiquitin-proteasome system (UPS) in cardiac diseases. Anti-hypertrophic effects and improved cardiac function have been reported after treatment with proteasome inhibitors in experimental models of cardiac hypertrophy. Here we tested whether proteasome inhibition could also reverse the disease phenotype in a genetically-modified mouse model of hypertrophic cardiomyopathy (HCM), which carries a mutation in Mybpc3, encoding the myofilament protein cardiac myosin-binding protein C. At 7 weeks of age, homozygous mutant mice (KI) have 39% higher left ventricular mass-to-body-weight ratio and 29% lower fractional area shortening (FAS) than wild-type (WT) mice. Both groups were treated with epoxomicin (0.5 mg/kg/day) or vehicle for 1 week via osmotic minipumps. Epoxomicin inhibited the chymotrypsin-like activity by ~50% in both groups. All parameters of cardiac hypertrophy (including the fetal gene program) were not affected by epoxomicin treatment in both groups. In contrast, FAS was 12% and 35% higher in epoxomicin-treated than vehicle-treated WT and KI mice, respectively. To identify which genes or pathways could be involved in this positive effect, we performed a transcriptome analysis in KI and WT neonatal cardiac myocytes, treated or not with the proteasome inhibitor MG132 (1 μM, 24 h). This revealed 103 genes (four-fold difference; 5% FDR) which are commonly regulated in both KI and WT cardiac myocytes. Thus, even in genetically-modified mice with manifest HCM, proteasome inhibition showed beneficial effects, at least with regard to cardiac function. Targeting the UPS in cardiac diseases remains therefore a therapeutic option.

Highlights

Along with the autophagy-lysosome pathway, the ubiquitinproteasome system (UPS) represents the major proteolytic system of eukaryotic cells and degrades highly selectively intracellular cytosolic, nuclear and myofibrillar proteins
We tested whether proteasome inhibition could reverse the disease phenotype in a genetically-modified mouse model of hypertrophic cardiomyopathy (HCM), which carries a mutation in Mybpc3, encoding the myofilament protein cardiac myosin-binding protein C
MARKED AND SIGNIFICANT DIFFERENTIAL GENE EXPRESSION IN CARDIAC MYOCYTES AFTER PROTEASOME INHIBITION To assess whether specific genes or biological pathways could be involved in the improved cardiac function, we performed a DISCUSSION In the present study we evaluated the cardiac phenotype after 1 week of proteasome inhibition in adolescent homozygous Mybpc3-targeted KI and corresponding WT mice

Summary

Introduction

Along with the autophagy-lysosome pathway, the ubiquitinproteasome system (UPS) represents the major proteolytic system of eukaryotic cells and degrades highly selectively intracellular cytosolic, nuclear and myofibrillar proteins. The eukaryotic 26S proteasome itself is composed of the 19S regulatory particle, which recognizes, deubiquitinates and unfolds the target protein, and the 20S core, which degrades the target protein through three distinct proteolytic activities (chymotrypsin-like, trypsin-like, and caspase-like). These proteolytic activities can be inhibited either reversibly by peptide aldehydes and peptide boronates (e.g., bortezomib) or irreversibly by β-lactones (e.g., PS-519) and epoxyketones (e.g., epoxomicin; Kisselev et al, 2012). In the case of an activated UPS, partial and short-term proteasome inhibition has shown beneficial effects in different animal models. In addition to its hypertrophy-preventing effect, proteasome inhibition has been shown to be even capable to www.frontiersin.org

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