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Schlossarek S, Singh SR, Geertz B, et al. Proteasome inhibition slightly improves cardiac function in mice with hypertrophic cardiomyopathy. Front Physiol. 2014;5:484doi: 10.3389/fphys.2014.00484.
Schlossarek, S., Singh, S. R., Geertz, B., Schulz, H., Reischmann, S., Hübner, N., & Carrier, L. (2014). Proteasome inhibition slightly improves cardiac function in mice with hypertrophic cardiomyopathy. Frontiers in physiology, 5484. https://doi.org/10.3389/fphys.2014.00484
Schlossarek, Saskia, et al. "Proteasome inhibition slightly improves cardiac function in mice with hypertrophic cardiomyopathy." Frontiers in physiology vol. 5 (2014): 484. doi: https://doi.org/10.3389/fphys.2014.00484
Schlossarek S, Singh SR, Geertz B, Schulz H, Reischmann S, Hübner N, Carrier L. Proteasome inhibition slightly improves cardiac function in mice with hypertrophic cardiomyopathy. Front Physiol. 2014 Dec 16;5:484. doi: 10.3389/fphys.2014.00484. eCollection 2014. PMID: 25566086; PMCID: PMC4267180.
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Front Physiol. 2014 Dec 16;5:484. doi: 10.3389/fphys.2014.00484. eCollection 2014.

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

Frontiers in physiology

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

Affiliations

  1. Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf Hamburg, Germany ; German Centre for Cardiovascular Research (DZHK) Hamburg/Kiel/Lübeck, Germany.
  2. Max-Delbrück-Center for Molecular Medicine (MDC) Berlin, Germany ; German Centre for Cardiovascular Research (DZHK) Berlin, Germany.

PMID: 25566086 PMCID: PMC4267180 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.

Keywords: Mybpc3; cardiomyopathy; hypertrophic; proteasome inhibitors; transgenic mice; ubiquitin-proteasome system

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