Primary proteasome inhibition results in cardiac dysfunction.

Abstract

AIMS:

The 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 RESULTS:

Female 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.

CONCLUSION:

The 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.

• Authors: Joerg Herrmann, Christine Wohlert, Ardan M Saguner, Ana Flores, Lisa L Nesbitt, Alejandro Chade, Lilach O Lerman, Amir Lerman
• Journal: European journal of heart failure (Eur J Heart Fail) Vol. 15 Issue 6 Pg. 614-23 (Jun 2013) ISSN: 1879-0844 [Electronic] England
• PMID: 23616520 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Boronic Acids
• Cardiotonic Agents
• Dipeptides
• N-(4-morpholine)carbonyl-beta-(1-naphthyl)-alanyl-leucine boronic acid
• Proteasome Inhibitors
• Vasodilator Agents
• Dobutamine
• Proteasome Endopeptidase Complex
• Adenosine

Topics

• Adenosine (pharmacology)
• Animals
• Boronic Acids (pharmacology)
• Capillary Permeability (drug effects)
• Cardiotonic Agents (pharmacology)
• Dipeptides (pharmacology)
• Dobutamine (pharmacology)
• Female
• Heart (drug effects, physiopathology)
• In Situ Nick-End Labeling
• Myocardial Perfusion Imaging
• Proteasome Endopeptidase Complex (drug effects, metabolism)
• Proteasome Inhibitors (pharmacology)
• Stroke Volume (drug effects)
• Swine
• Tomography, X-Ray Computed
• Vasodilator Agents (pharmacology)
• Ventricular Function, Left (drug effects)