MAO inhibition preserves mitochondria-endoplasmic reticulum homeostasis, prevents mast cell degranulation and improves diastolic function in type 1 diabetes

18 Jun 2018

Cardiovascular disease is the leading cause of mortality among diabetic patients. Inflammation, reactive oxygen species (ROS) levels, mitochondrial dysfunction and endoplasmic reticulum (ER) stress play a critical role in the pathogenesis of diabetic cardiomyopathy. Yet, the precise interplay between these factors remains elusive. Here we show that mitochondrial flavoenzymes monoamine oxidases (MAOs) contribute to increased ROS levels and mitochondrial dysfunction in primary cardiomyocytes exposed to high glucose and pro-inflammatory stimuli. These events occur upstream of ER stress and are abolished upon MAOs inhibition, highlighting for the first time the role of these flavoenzymes in the cross-talk between mitochondria and ER. Importantly, administration of a MAO inhibitor to streptozotocin-treated mice completely prevented heart failure with preserved ejection fraction, oxidative changes and ER stress in the myocardial tissue. Moreover, we show that MAO activity contributes to cardiac fibrosis and mast cell degranulation, processes involved in cardiac remodeling. Taken together, these results clearly show the critical role of MAOs in diabetic cardiomyopathy and provide novel insights into the mechanisms underlying MAO-induced changes in the diabetic heart.