Monoamine Oxidase A–Mediated Enhanced Catabolism of Norepinephrine Contributes to Adverse Remodeling and Pump Failure in Hearts With Pressure Overload

Kaludercic, Nina; Takimoto, Eiki; Nagayama, Takahiro; Feng, Ning; Lai, Edwin W.; Bedja, Djahida; Chen, Kevin; Gabrielson, Kathleen L.; Blakely, Randy D.; Shih, Jean C.; Pacák, Karel; Kass, David A.; Lisa, Fabio Di; Paolocci, Nazareno

doi:10.1161/circresaha.109.198366

Cited by 192 publications

(199 citation statements)

References 49 publications

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“…This event, in turn, enhances the catabolic capacity of MAO isoenzymes. Consistent with this scenario, our recent findings demonstrate that pharmacological or genetic inhibition of MAO-A prevents the occurrence of heart failure in pressure-overloaded mice (25). This salutary action stems from both the prevention of H 2 O 2 -driven oxidative stress/tissue apoptosis in the cardiac muscle, and the improved bio-availability of intra-neuronal norepinephrine.…”

supporting

confidence: 67%

“…However, in stark contrast to WT, MAO-B -/ -mice displayed compensated LV function. Typically, 9 weeks after TAC hearts undergo overt LV remodeling and exhibit pump dysfunction (25,37), as was the case with WT mice. In these mice, TAC produced an enlargement of LV end-systolic and end-diastolic diameters, consistent with the occurrence of LV dilation at this stage in other mouse strains (37).…”

Section: Mao-bmentioning

confidence: 97%

“…Together, these events concur to maintain proper left ventricular (LV) morphology and function, even under conditions of chronic cardiac stress due to pressure overload (3,4,39). As a major source of reactive oxygen species (ROS), MAO-A contributes to in vitro myocyte hypertrophy (6), ischemia/reperfusion (I/R) injury both in ex vivo (10) and in vivo models (5,31), heart failure and LV remodeling (25,42).…”

mentioning

confidence: 99%

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Monoamine Oxidase B Prompts Mitochondrial and Cardiac Dysfunction in Pressure Overloaded Hearts

Kaludercic

Carpi

Nagayama

et al. 2014

Antioxidants & Redox Signaling

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140

139

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Aims: Monoamine oxidases (MAOs) are mitochondrial flavoenzymes responsible for neurotransmitter and biogenic amines catabolism. MAO-A contributes to heart failure progression via enhanced norepinephrine catabolism and oxidative stress. The potential pathogenetic role of the isoenzyme MAO-B in cardiac diseases is currently unknown. Moreover, it is has not been determined yet whether MAO activation can directly affect mitochondrial function. Results: In wild type mice, pressure overload induced by transverse aortic constriction (TAC) resulted in enhanced dopamine catabolism, left ventricular (LV) remodeling, and dysfunction. Conversely, mice lacking MAO-B (MAO-B -/ -) subjected to TAC maintained concentric hypertrophy accompanied by extracellular signal regulated kinase (ERK)1/2 activation, and preserved LV function, both at early (3 weeks) and late stages (9 weeks). Enhanced MAO activation triggered oxidative stress, and dropped mitochondrial membrane potential in the presence of ATP synthase inhibitor oligomycin both in neonatal and adult cardiomyocytes. The MAO-B inhibitor pargyline completely offset this change, suggesting that MAO activation induces a latent mitochondrial dysfunction, causing these organelles to hydrolyze ATP. Moreover, MAO-dependent aldehyde formation due to inhibition of aldehyde dehydrogenase 2 activity also contributed to alter mitochondrial bioenergetics. Innovation: Our study unravels a novel role for MAO-B in the pathogenesis of heart failure, showing that both MAO-driven reactive oxygen species production and impaired aldehyde metabolism affect mitochondrial function. Conclusion: Under conditions of chronic hemodynamic stress, enhanced MAO-B activity is a major determinant of cardiac structural and functional disarrangement. Both increased oxidative stress and the accumulation of aldehyde intermediates are likely liable for these adverse morphological and mechanical changes by directly targeting mitochondria. Antioxid. Redox Signal. 20, 267-280.

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supporting

confidence: 67%

Section: Mao-bmentioning

confidence: 97%

mentioning

confidence: 99%

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Monoamine Oxidase B Prompts Mitochondrial and Cardiac Dysfunction in Pressure Overloaded Hearts

Kaludercic

Carpi

Nagayama

et al. 2014

Antioxidants & Redox Signaling

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140

139

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“…In the heart, MAO‐A has been demonstrated to be an important source of oxidative stress in acute and chronic pathological conditions (Bianchi et al, 2005; Kaludercic et al, 2010). In particular, cardiac overexpression of MAO‐A drives oxidative stress and mitochondrial damage, leading to cell death and heart failure (Kaludercic, Mialet‐Perez, Paolocci, Parini, & Di Lisa, 2014; Villeneuve et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

et al. 2018

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Cellular senescence, the irreversible cell cycle arrest observed in somatic cells, is an important driver of age‐associated diseases. Mitochondria have been implicated in the process of senescence, primarily because they are both sources and targets of reactive oxygen species (ROS). In the heart, oxidative stress contributes to pathological cardiac ageing, but the mechanisms underlying ROS production are still not completely understood. The mitochondrial enzyme monoamine oxidase‐A (MAO‐A) is a relevant source of ROS in the heart through the formation of H2O2 derived from the degradation of its main substrates, norepinephrine (NE) and serotonin. However, the potential link between MAO‐A and senescence has not been previously investigated. Using cardiomyoblasts and primary cardiomyocytes, we demonstrate that chronic MAO‐A activation mediated by synthetic (tyramine) and physiological (NE) substrates induces ROS‐dependent DNA damage response, activation of cyclin‐dependent kinase inhibitors p21cip, p16ink4a, and p15ink4b and typical features of senescence such as cell flattening and SA‐β‐gal activity. Moreover, we observe that ROS produced by MAO‐A lead to the accumulation of p53 in the cytosol where it inhibits parkin, an important regulator of mitophagy, resulting in mitochondrial dysfunction. Additionally, we show that the mTOR kinase contributes to mitophagy dysfunction by enhancing p53 cytoplasmic accumulation. Importantly, restoration of mitophagy, either by overexpression of parkin or inhibition of mTOR, prevents mitochondrial dysfunction and induction of senescence. Altogether, our data demonstrate a novel link between MAO‐A and senescence in cardiomyocytes and provides mechanistic insights into the potential role of MAO‐dependent oxidative stress in age‐related pathologies.

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“…In cardiac myocytes, ROS are a byproduct of mitochondrial electron transport (5) and are also produced by extramitochondrial sources, including NADPH oxidase (1), uncoupled nitric oxide synthase (6), xanthine oxidase (7), and monoamine oxidase (8,9). Both mitochondrial and extramitochondrial sources have been implicated in cardiac disorders including heart failure, myocardial ischemia, and arrhythmias.…”

mentioning

confidence: 99%

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

Dey

Sidor

O’Rourke

2016

Journal of Biological Chemistry

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Oxidative stress arises from an imbalance in the production and scavenging rates of reactive oxygen species (ROS) and is a key factor in the pathophysiology of cardiovascular disease and aging. The presence of parallel pathways and multiple intracellular compartments, each having its own ROS sources and antioxidant enzymes, complicates the determination of the most important regulatory nodes of the redox network. Here we quantified ROS dynamics within specific intracellular compartments in the cytosol and mitochondria and determined which scavenging enzymes exert the most control over antioxidant fluxes in H9c2 cardiac myoblasts. We used novel targeted viral gene transfer vectors expressing redox-sensitive GFP fused to sensor domains to measure H 2 O 2 or oxidized glutathione. Using genetic manipulation in heart-derived H9c2 cells, we explored the contribution of specific antioxidant enzymes to ROS scavenging and glutathione redox potential within each intracellular compartment. Our findings reveal that antioxidant flux is strongly dependent on mitochondrial substrate catabolism, with availability of NADPH as a major rate-controlling step. Moreover, ROS scavenging by mitochondria significantly contributes to cytoplasmic ROS handling. The findings provide fundamental information about the control of ROS scavenging by the redox network and suggest novel interventions for circumventing oxidative stress in cardiac cells. Reactive oxygen species (ROS)2 serve as both signaling molecules and destructive agents, requiring cells to finely regulate their levels. Antioxidant enzymes catalyze ROS conversion directly via an active-site metal ion (e.g. superoxide dismutase or catalase) or through pathways involving the donation of an electron from the moiety-conserved redox couples thioredoxin and glutathione, which require continuous regeneration of the reduced species. Uncontrolled or uncontained ROS accumulation can affect numerous cell functions, including gene/protein expression, calcium handling, myofilament activation, bioenergetics, and substrate metabolism (1-4). Different ROS-generating and scavenging systems are present in distinct cellular compartments, and these may interact in complex ways that have not been well characterized.In cardiac myocytes, ROS are a byproduct of mitochondrial electron transport (5) and are also produced by extramitochondrial sources, including NADPH oxidase (1), uncoupled nitric oxide synthase (6), xanthine oxidase (7), and monoamine oxidase (8, 9). Both mitochondrial and extramitochondrial sources have been implicated in cardiac disorders including heart failure, myocardial ischemia, and arrhythmias. The dynamics and steady-state levels of ROS in local intracellular domains are determined by the rates of free radical generation and scavenging. Failure to scavenge free radicals via antioxidant fluxes can trigger a vicious cycle of dysfunction, leading to death (10). Recent studies have demonstrated that antioxidant enzymes targeted to the mitochondria, but not the cytoplasm, protect agai...

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Monoamine Oxidase A–Mediated Enhanced Catabolism of Norepinephrine Contributes to Adverse Remodeling and Pump Failure in Hearts With Pressure Overload

Cited by 192 publications

References 49 publications

Monoamine Oxidase B Prompts Mitochondrial and Cardiac Dysfunction in Pressure Overloaded Hearts

Monoamine Oxidase B Prompts Mitochondrial and Cardiac Dysfunction in Pressure Overloaded Hearts

Monoamine oxidase‐A is a novel driver of stress‐induced premature senescence through inhibition of parkin‐mediated mitophagy

Compartment-specific Control of Reactive Oxygen Species Scavenging by Antioxidant Pathway Enzymes

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