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

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.

Tumor Necrosis Factor Receptor-Associated Protein 1 Protects against Mitochondrial Injury by Preventing High Glucose-Induced mPTP Opening in Diabetes

“…It has been reported to be regulated by TRAP1 in hypoxic injury [10]. Opening of the mPTP is a key prerequisite for the induction of mitochondrial-mediated apoptosis and is of critical importance during HG injury [45]. According to our results, TRAP1 inhibited mPTP opening, which may be the mechanism by which TRAP1 protects mitochondria against HG-induced stress.…”

On the Clinical Pharmacology of Reactive Oxygen Species

“…MAOs exist in two isoforms, A and B, which differ in structure, substrate preference, inhibitor specificity, and tissue distribution (Binda et al, 2002;De Colibus et al, 2005;Finberg, 2014). MAO-dependent increases in H 2 O 2 formation have been observed in isolated skeletal and cardiac myocytes (Kaludercic et al, 2010(Kaludercic et al, , 2014Sorato et al, 2014;Deshwal et al, 2018); increased expression of MAO-B, but not MAO-A, has been observed in various other tissues upon aging, including brain (Fowler et al, 1997).…”

“…Several reports suggest that, in addition to modulating neurotransmitter levels, MAO-dependent ROS generation promotes the development of neurodegenerative disorders by causing oxidative damage to neurons (Youdim et al, 2006;Bortolato et al, 2008). Additionally, MAO contributes to cardiovascular disease, including ischemia-reperfusion injury (Bianchi et al, 2005;Pchejetski et al, 2007;Carpi et al, 2009), pressure overload (Kaludercic et al, 2010(Kaludercic et al, , 2014, diabetic cardiomyopathy (Deshwal et al, 2018), postoperative atrial fibrillation (Anderson et al, 2014), and vascular dysfunction (Sturza et al, 2013). MAO activity is increased in the left and right ventricles from patients with ischemic heart disease (Manni et al, 2016).…”

(Pro)renin Receptor is Involved in Myocardial Damage in Alcoholic Cardiomyopathy

“…Toxic acetaldehyde formed in the ischemic–reperfused (I/R) heart causes mast cell degranulation, which leads to angiotensin‐induced NE sympathetic release and severe arrhythmia (Marino et al., ). Despite the numerous biological functions of mast cells, there is no sufficient evidence for a direct mechanism of degranulation (Deshwal et al., ). Herein, we reported that alcohol intake increased mast cell number and degranulation, which deteriorated the cardiac inflammation response.…”

“…The secondary antibody incubation and DAB color development were performed following the manufacturer's instructions (ZSGB‐Bio). Mast cell density and degranulation were detected by toluidine blue staining (0.1%, for 45 min) as described (Deshwal et al., ). Degranulation of mast cells was quantified by counting the total number of cells per field.…”