Fibrosis Rescue Improves Cardiac Function in Dystrophin-Deficient Mice and Duchenne Patient-Specific Cardiomyocytes by Immunoproteasome Modulation

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Abstract

Patients affected by Duchenne muscular dystrophy (DMD) develop a progressive dilated cardiomyopathy characterized by inflammatory cell infiltration, necrosis, and cardiac fibrosis. Standard treatments consider the use of β-blockers and angiotensin-converting enzyme inhibitors that are symptomatic and unspecific toward DMD disease. Medications that target DMD cardiac fibrosis are in the early stages of development. We found immunoproteasome dysregulation in affected hearts of mdx mice (murine animal model of DMD) and cardiomyocytes derived from induced pluripotent stem cells of patients with DMD. Interestingly, immunoproteasome inhibition ameliorated cardiomyopathy in mdx mice and reduced the development of cardiac fibrosis. Establishing the immunoproteasome inhibition-dependent cardioprotective role suggests the possibility of modulating the immunoproteasome as new and clinically relevant treatment to rescue dilated cardiomyopathy in patients with DMD.

Original languageEnglish
JournalAmerican Journal of Pathology
DOIs
Publication statusE-pub ahead of print - Nov 16 2018

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Dystrophin
Duchenne Muscular Dystrophy
Cardiac Myocytes
Fibrosis
Inbred mdx Mouse
Dilated Cardiomyopathy
Induced Pluripotent Stem Cells
Muscular Diseases
Cardiomyopathies
Angiotensin-Converting Enzyme Inhibitors
Necrosis
Animal Models
Therapeutics

Cite this

@article{98bc47354a67467e906f6ebff22421ff,
title = "Fibrosis Rescue Improves Cardiac Function in Dystrophin-Deficient Mice and Duchenne Patient-Specific Cardiomyocytes by Immunoproteasome Modulation",
abstract = "Patients affected by Duchenne muscular dystrophy (DMD) develop a progressive dilated cardiomyopathy characterized by inflammatory cell infiltration, necrosis, and cardiac fibrosis. Standard treatments consider the use of β-blockers and angiotensin-converting enzyme inhibitors that are symptomatic and unspecific toward DMD disease. Medications that target DMD cardiac fibrosis are in the early stages of development. We found immunoproteasome dysregulation in affected hearts of mdx mice (murine animal model of DMD) and cardiomyocytes derived from induced pluripotent stem cells of patients with DMD. Interestingly, immunoproteasome inhibition ameliorated cardiomyopathy in mdx mice and reduced the development of cardiac fibrosis. Establishing the immunoproteasome inhibition-dependent cardioprotective role suggests the possibility of modulating the immunoproteasome as new and clinically relevant treatment to rescue dilated cardiomyopathy in patients with DMD.",
author = "Andrea Farini and Aoife Gowran and Pamela Bella and Clementina Sitzia and Alessandro Scopece and Elisa Castiglioni and Davide Rovina and Patrizia Nigro and Chiara Villa and Francesco Fortunato and Comi, {Giacomo Pietro} and Giuseppina Milano and Giulio Pompilio and Yvan Torrente",
note = "Copyright {\circledC} 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = "11",
day = "16",
doi = "10.1016/j.ajpath.2018.10.010",
language = "English",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",

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TY - JOUR

T1 - Fibrosis Rescue Improves Cardiac Function in Dystrophin-Deficient Mice and Duchenne Patient-Specific Cardiomyocytes by Immunoproteasome Modulation

AU - Farini, Andrea

AU - Gowran, Aoife

AU - Bella, Pamela

AU - Sitzia, Clementina

AU - Scopece, Alessandro

AU - Castiglioni, Elisa

AU - Rovina, Davide

AU - Nigro, Patrizia

AU - Villa, Chiara

AU - Fortunato, Francesco

AU - Comi, Giacomo Pietro

AU - Milano, Giuseppina

AU - Pompilio, Giulio

AU - Torrente, Yvan

N1 - Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

PY - 2018/11/16

Y1 - 2018/11/16

N2 - Patients affected by Duchenne muscular dystrophy (DMD) develop a progressive dilated cardiomyopathy characterized by inflammatory cell infiltration, necrosis, and cardiac fibrosis. Standard treatments consider the use of β-blockers and angiotensin-converting enzyme inhibitors that are symptomatic and unspecific toward DMD disease. Medications that target DMD cardiac fibrosis are in the early stages of development. We found immunoproteasome dysregulation in affected hearts of mdx mice (murine animal model of DMD) and cardiomyocytes derived from induced pluripotent stem cells of patients with DMD. Interestingly, immunoproteasome inhibition ameliorated cardiomyopathy in mdx mice and reduced the development of cardiac fibrosis. Establishing the immunoproteasome inhibition-dependent cardioprotective role suggests the possibility of modulating the immunoproteasome as new and clinically relevant treatment to rescue dilated cardiomyopathy in patients with DMD.

AB - Patients affected by Duchenne muscular dystrophy (DMD) develop a progressive dilated cardiomyopathy characterized by inflammatory cell infiltration, necrosis, and cardiac fibrosis. Standard treatments consider the use of β-blockers and angiotensin-converting enzyme inhibitors that are symptomatic and unspecific toward DMD disease. Medications that target DMD cardiac fibrosis are in the early stages of development. We found immunoproteasome dysregulation in affected hearts of mdx mice (murine animal model of DMD) and cardiomyocytes derived from induced pluripotent stem cells of patients with DMD. Interestingly, immunoproteasome inhibition ameliorated cardiomyopathy in mdx mice and reduced the development of cardiac fibrosis. Establishing the immunoproteasome inhibition-dependent cardioprotective role suggests the possibility of modulating the immunoproteasome as new and clinically relevant treatment to rescue dilated cardiomyopathy in patients with DMD.

U2 - 10.1016/j.ajpath.2018.10.010

DO - 10.1016/j.ajpath.2018.10.010

M3 - Article

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

ER -