Universität zu Köln

Deshwal, Soni, Forkink, Marleen, Hu, Chou-Hui, Buonincontri, Guido, Antonucci, Salvatore, Di Sante, Moises, Murphy, Michael P., Paolocci, Nazareno, Mochly-Rosen, Daria, Krieg, Thomas ORCID: 0000-0002-5192-580X, Di Lisa, Fabio and Kaludercic, Nina (2018). Monoamine oxidase-dependent endoplasmic reticulum-mitochondria dysfunction and mast cell degranulation lead to adverse cardiac remodeling in diabetes. Cell Death Differ., 25 (9). S. 1518 - 1533. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5403

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Deshwal, Soni UNSPECIFIED UNSPECIFIED UNSPECIFIED Forkink, Marleen UNSPECIFIED UNSPECIFIED UNSPECIFIED Hu, Chou-Hui UNSPECIFIED UNSPECIFIED UNSPECIFIED Buonincontri, Guido UNSPECIFIED UNSPECIFIED UNSPECIFIED Antonucci, Salvatore UNSPECIFIED UNSPECIFIED UNSPECIFIED Di Sante, Moises UNSPECIFIED UNSPECIFIED UNSPECIFIED Murphy, Michael P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Paolocci, Nazareno UNSPECIFIED UNSPECIFIED UNSPECIFIED Mochly-Rosen, Daria UNSPECIFIED UNSPECIFIED UNSPECIFIED Krieg, Thomas UNSPECIFIED orcid.org/0000-0002-5192-580X UNSPECIFIED Di Lisa, Fabio UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaludercic, Nina UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-174618
DOI:	10.1038/s41418-018-0071-1
Journal or Publication Title:	Cell Death Differ.
Volume:	25
Number:	9
Page Range:	S. 1518 - 1533
Date:	2018
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5403
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PERMEABILITY TRANSITION PORE; ENDOTHELIAL DYSFUNCTION; GLUTATHIONE-PEROXIDASE; OXIDATIVE STRESS; ATP SYNTHASE; HEART; CARDIOMYOPATHY; OVEREXPRESSION; DISEASE; GLUCOSE Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17461