Primary proteasome inhibition results in cardiac dysfunction

Joerg Herrmann, Christine Wohlert, Ardan M. Saguner, Ana Flores, Lisa L. Nesbitt, Alejandro Chade, Lilach O. Lerman, Amir Lerman

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

AimsThe proteasome prevents the intracellular accumulation of proteins and its impairment can lead to structural and functional alterations, as noted for the coronary vasculature in a previous study. Utilizing the same model, this study was designed to test the hypothesis that chronic proteasome inhibition (PSI) also leads to structural and functional changes of the heart.Methods and resultsFemale domestic pigs were randomized to a normal diet without (N) or with twice-weekly subcutaneous injections of the proteasome inhibitor MLN-273 (0.08 mg/kg, N + PSI, n = 5 each group). In vivo data on cardiac structure and function as well as myocardial perfusion and microvascular permeability response to adenosine and dobutamine were obtained by electron beam computed tomography after 11 weeks. Subsequent ex vivo myocardial analyses included immunoblotting, immunostaining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labelling), Masson trichrome, and Congo red staining. Compared with N, an increase in LV mass was observed in N + PSI (106.5 ± 16.4 g vs. 183.1 ± 24.2 g, P < 0.05). The early to late diastolic filling ratio was increased in N + PSI vs. N (3.5 ± 0.6 vs. 1.8 ± 0.1, P < 0.05). The EF tended to be lower (46 ± 12% and 53 ± 9%, respectively) and cardiac output was significantly lower in N + PSI than in N (2.9 ± 1.1 vs. 4.7 ± 1.1 L/min, P < 0.05). Tissue analyses demonstrated an accumulation of proteasome substrates, apoptosis, and fibrosis in the PSI group. Compared with N, the myocardial perfusion response was reduced and microvascular permeability was increased in N + PSI.ConclusionThe current study demonstrates that chronic proeasome inhibition affects the cardiovascular system, leading to functional and structural alteration of the heart consistent with a hypertrophic-restrictive cardiomyopathy phenotype. All rights reserved.

Original languageEnglish (US)
Pages (from-to)614-623
Number of pages10
JournalEuropean Journal of Heart Failure
Volume15
Issue number6
DOIs
StatePublished - Jun 2013

Keywords

  • Cardiomyopathy
  • Heart failure
  • Proteasome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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