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.
Highlights
Monoamine oxidase (MAO) account for reactive oxygen species (ROS) formation in isolated cardiomyocytes exposed to high glucose (HG) and proinflammatory cytokine IL-1β
The present results demonstrate that MAO-induced ROS formation causes mitochondrial dysfunction and endoplasmic reticulum (ER) stress, factors that promote Diabetic cardiomyopathy (DCM) development (Fig. 7)
Other studies have shown that diabetes-induced mitochondrial dysfunction and ROS formation occur through calpain [41] and O-linked β-N-acetylglucosamine glycosylation [42]
Summary
Cardiovascular complications account for the high morbidity and mortality in patients with type 1 and type 2 diabetes (T1D, T2D) [1]. Diabetic cardiomyopathy (DCM) is a distinct myocardial disease, characterized by structural changes in the heart and diastolic/systolic dysfunction. Several factors, including reactive oxygen species (ROS) formation and mitochondrial dysfunction, contribute to hyperglycemia-. MD 21205, USA 6 Department of Experimental Medicine, University of Perugia, 06123 Perugia, Italy 7 Department of Chemical and Systems Biology, School of Medicine, Stanford University, Stanford, CA 94305-5174, USA 8 Present address: Institute for Genetics, University of Cologne, Official journal of the Cell Death Differentiation Association. ROS formation in control or MAO-A siRNA-treated cells was assessed upon treatment with NG or HG in the absence or presence of IL-1β (i). 100 cells were analyzed per condition in each experiment and all the experiments were performed at least three times. Two-way ANOVA test followed by post hoc Tukey’s (b and i) or Dunn’s (e) multiple comparison test (*p < 0.05 vs NG vehicle, #p < 0.05 vs HG vehicle and §p < 0.05 vs HG-IL1β)
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