Monoamine oxidase-dependent endoplasmic reticulum-mitochondria dysfunction and mast cell degranulation lead to adverse cardiac remodeling in diabetes

Soni Deshwal, Marleen Forkink, Chou Hui Hu, Guido Buonincontri, Salvatore Antonucci, Moises Di Sante, Michael P. Murphy, Nazareno Paolocci, Daria Mochly-Rosen, Thomas Krieg, Fabio Di Lisa, Nina Kaludercic

Research output: Contribution to journalArticle

Abstract

Monoamine oxidase (MAO) inhibitors ameliorate contractile function in diabetic animals, but the mechanisms remain unknown. Equally elusive is the interplay between the cardiomyocyte alterations induced by hyperglycemia and the accompanying inflammation. Here we show that exposure of primary cardiomyocytes to high glucose and pro-inflammatory stimuli leads to MAO-dependent increase in reactive oxygen species that causes permeability transition pore opening and mitochondrial dysfunction. These events occur upstream of endoplasmic reticulum (ER) stress and are abolished by the MAO inhibitor pargyline, highlighting the role of these flavoenzymes in the ER/mitochondria cross-talk. In vivo, streptozotocin administration to mice induced oxidative changes and ER stress in the heart, events that were abolished by pargyline. Moreover, MAO inhibition prevented both mast cell degranulation and altered collagen deposition, thereby normalizing diastolic function. Taken together, these results elucidate the mechanisms underlying MAO-induced damage in diabetic cardiomyopathy and provide novel evidence for the role of MAOs in inflammation and inter-organelle communication. MAO inhibitors may be considered as a therapeutic option for diabetic complications as well as for other disorders in which mast cell degranulation is a dominant phenomenon.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalCell Death and Differentiation
DOIs
StateAccepted/In press - Feb 19 2018

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Cell Degranulation
Monoamine Oxidase
Mast Cells
Endoplasmic Reticulum
Monoamine Oxidase Inhibitors
Mitochondria
Pargyline
Endoplasmic Reticulum Stress
Cardiac Myocytes
Diabetic Cardiomyopathies
Inflammation
Diabetes Complications
Streptozocin
Hyperglycemia
Organelles
Reactive Oxygen Species
Collagen
Communication
Glucose
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Monoamine oxidase-dependent endoplasmic reticulum-mitochondria dysfunction and mast cell degranulation lead to adverse cardiac remodeling in diabetes. / Deshwal, Soni; Forkink, Marleen; Hu, Chou Hui; Buonincontri, Guido; Antonucci, Salvatore; Di Sante, Moises; Murphy, Michael P.; Paolocci, Nazareno; Mochly-Rosen, Daria; Krieg, Thomas; Di Lisa, Fabio; Kaludercic, Nina.

In: Cell Death and Differentiation, 19.02.2018, p. 1-15.

Research output: Contribution to journalArticle

Deshwal, S, Forkink, M, Hu, CH, Buonincontri, G, Antonucci, S, Di Sante, M, Murphy, MP, Paolocci, N, Mochly-Rosen, D, Krieg, T, Di Lisa, F & Kaludercic, N 2018, 'Monoamine oxidase-dependent endoplasmic reticulum-mitochondria dysfunction and mast cell degranulation lead to adverse cardiac remodeling in diabetes', Cell Death and Differentiation, pp. 1-15. https://doi.org/10.1038/s41418-018-0071-1
Deshwal, Soni ; Forkink, Marleen ; Hu, Chou Hui ; Buonincontri, Guido ; Antonucci, Salvatore ; Di Sante, Moises ; Murphy, Michael P. ; Paolocci, Nazareno ; Mochly-Rosen, Daria ; Krieg, Thomas ; Di Lisa, Fabio ; Kaludercic, Nina. / Monoamine oxidase-dependent endoplasmic reticulum-mitochondria dysfunction and mast cell degranulation lead to adverse cardiac remodeling in diabetes. In: Cell Death and Differentiation. 2018 ; pp. 1-15.
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