Repository logo

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

Published version

Change log


Deshwal, Soni 
Forkink, Marleen 
Hu, Chou-Hui 
Buonincontri, Guido 
Antonucci, Salvatore 


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.



Animals, Cell Degranulation, Diabetes Mellitus, Experimental, Endoplasmic Reticulum Stress, Glucose, Interleukin-1beta, Male, Mice, Mice, Inbred C57BL, Mitochondria, Mitochondrial Membrane Transport Proteins, Mitochondrial Permeability Transition Pore, Monoamine Oxidase, Monoamine Oxidase Inhibitors, Muscle Cells, Myocardium, RNA Interference, RNA, Small Interfering, Rats, Reactive Oxygen Species, Ventricular Remodeling

Journal Title

Cell Death Differ

Conference Name

Journal ISSN


Volume Title



Springer Science and Business Media LLC
European Commission (316738)
Medical Research Council (MC_U105663142)
Medical Research Council (MC_UU_00015/3)
Wellcome Trust (110159/Z/15/Z)